Ethers, secondary amines and derivatives thereof as modulators of the 5-HT2A serotonin receptor useful for the treatment of disorders related thereto

ABSTRACT

The present invention pertains to certain compounds of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the 5-HT 2A  serotonin receptor. 
                         
Compounds and pharmaceutical compositions thereof are directed to methods useful in the treatment of platelet aggreagation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, blood clot formation, asthma or symptoms thereof, agitation or a symptom thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette&#39;s syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, and sleep disorders, sleep disorders, diabetic-related disorders, progressive multifocal leukoencephalopathy and the like.
 
     The present invention also relates to the methods for the treatment of 5-HT 2A  serotonin receptor associated disorders in combination with other pharmaceutical agents administered separately or together.

FIELD OF THE INVENTION

The present invention pertains to certain compounds of Formula (Ia) andpharmaceutical compositions thereof that modulate the activity of the5-HT_(2A) serotonin receptor. Compounds and pharmaceutical compositionsthereof are directed to methods useful in the treatment of plateletaggregation, coronary artery disease, myocardial infarction, transientischemic attack, angina, stroke, atrial fibrillation, blood clotformation, asthma or symptoms thereof, agitation or a symptom thereof,behavioral disorders, drug induced psychosis, excitative psychosis,Gilles de la Tourette's syndrome, manic disorder, organic or NOSpsychosis, psychotic disorder, psychosis, acute schizophrenia, chronicschizophrenia, NOS schizophrenia and related disorders, sleep disorders,diabetic-related disorders, progressive multifocal leukoencephalopathyand the like.

The present invention also relates to the methods for the treatment of5-HT_(2A) serotonin receptor associated disorders in combination withother pharmaceutical agents administered separately or together.

BACKGROUND OF THE INVENTION

G Protein Coupled Receptors

G Protein coupled receptors share a common structural motif. All thesereceptors have seven sequences of between 22 to 24 hydrophobic aminoacids that form seven alpha helices, each of which spans the membrane.The transmembrane helices are joined by strands of amino acids having alarger loop between the fourth and fifth transmembrane helix on theextracellular side of the membrane. Another larger loop, composedprimarily of hydrophilic amino acids, joins transmembrane helices fiveand six on the intracellular side of the membrane. The carboxy terminusof the receptor lies intracellularly with the amino terminus in theextracellular space. It is thought that the loop joining helices fiveand six, as well as, the carboxy terminus, interact with the G protein.Currently, Gq, Gs, Gi and Go are G proteins that have been identified.

Under physiological conditions, G protein coupled receptors exist in thecell membrane in equilibrium between two different states orconformations: an “inactive” state and an “active” state. A receptor inan inactive state is unable to link to the intracellular transductionpathway to produce a biological response. Changing the receptorconformation to the active state allows linkage to the transductionpathway and produces a biological response.

A receptor may be stabilized in an active state by an endogenous ligandor an exogenous agonist ligand. Recent discoveries such as, includingbut not exclusively limited to, modifications to the amino acid sequenceof the receptor provide means other than ligands to stabilize the activestate conformation. These means effectively stabilize the receptor in anactive state by simulating the effect of a ligand binding to thereceptor. Stabilization by such ligand-independent means is termed“constitutive receptor activation.”

Serotonin Receptors

Receptors for serotonin (5-hydroxytryptamine, 5-HT) are an importantclass of G protein coupled receptors. Serotonin is thought to play arole in processes related to learning and memory, sleep,thermoregulation, mood, motor activity, pain, sexual and aggressivebehaviors, appetite, neurodegenerative regulation, and biologicalrhythms. Not surprisingly, serotonin is linked to pathophysiologicalconditions such as anxiety, depression, obsessive compulsive disorders,schizophrenia, suicide, autism, migraine, emesis, alcoholism, andneurodegenerative disorders. With respect to anti-psychotic treatmentapproaches focused on the serotonin receptors, these types oftherapeutics can generally be divided into two classes, the “typical”and the “atypical.” Both have anti-psychotic effects, but the typicalsalso include concomitant motor-related side effects (extra pyramidalsyndromes, e.g., lip-smacking, tongue darting, locomotor movement, etc).Such side effects are thought to be associated with the compoundsinteracting with other receptors, such as the human dopamine D₂ receptorin the nigro-striatal pathway. Therefore, an atypical treatment ispreferred. Haloperidol is considered a typical anti-psychotic, andclozapine is considered an atypical anti-psychotic.

Serotonin receptors are divided into seven subfamilies, referred to as5-HT₁ through 5-HT₇, inclusive. These subfamilies are further dividedinto subtypes. For example, the 5-HT₂ subfamily is divided into threereceptor subtypes: 5-HT_(2A), 5-HT_(2B), and 5-HT_(2C). The human5-HT_(2C) receptor was first isolated and cloned in 1987, and the human5-HT_(2A) receptor was first isolated and cloned in 1990. These tworeceptors are thought to be the site of action of hallucinogenic drugs.Additionally, antagonists to the 5-HT_(2A) and 5-HT_(2C) receptors arebelieved to be useful in treating depression, anxiety, psychosis, andeating disorders.

U.S. Pat. No. 4,985,352 describes the isolation, characterization, andexpression of a functional cDNA clone encoding the entire human5-HT_(1C) receptor (now known as the 5-HT_(2C) receptor). U.S. Pat. Nos.5,661,024 and 6,541,209 describe the isolation, characterization, andexpression of a functional cDNA clone encoding the entire human5-HT_(2A) receptor.

Mutations of the endogenous forms of the rat 5-HT_(2A) and rat 5-HT_(2C)receptors have been reported to lead to constitutive activation of thesereceptors (5-HT_(2A): Casey, C. et al. (1996) Society for NeuroscienceAbstracts, 22:699.10, hereinafter “Casey”; 5-HT_(2C): Herrick-Davis, K.,and Teitler, M. (1996) Society for Neuroscience Abstracts, 22:699.18,hereinafter “Herrick-Davis 1”; and Herrick-Davis, K. et al. (1997) J.Neurochemistry 69(3): 1138, hereinafter “Herrick-Davis-2”). Caseydescribes a mutation of the cysteine residue at position 322 of the rat5-HT_(2A) receptor to lysine (C322K), glutamine (C322Q), and arginine(C322R) which reportedly led to constitutive activation. Herrick-Davis 1and Herrick-Davis 2 describe mutations of the serine residue at position312 of the rat 5-HT_(2C) receptor to phenylalanine (S312F) and lysine(S312K), which reportedly led to constitutive activation.

SUMMARY OF THE INVENTION

One aspect of the present invention pertains to certain compounds asshown in Formula (Ia):

or a pharmaceutically acceptable salt, hydrate or solvate thereof;

wherein:

V is O or NH;

W is C₁₋₄ alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8substituents selected independently from the group consisting of C₁₋₃alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₃₋₇ cycloalkyl, C₁₋₃ haloalkyl,halogen, and oxo;

Q is —NR^(4a)R^(4b) or —OR^(4c), wherein:

R^(4a) is H or a metabolically-labile group;

R^(4b) is C₁₋₆ alkyl, aryl, C₃₋₇ cycloalkyl, C₁₋₆ haloalkyl,heterocyclyl, or heteroaryl, wherein each is optionally substituted with1, 2, 3, 4, or 5 substituents selected independently from the groupconsisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,C₁₋₄ alkylthio, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl, imino, nitro,sulfonamide and phenyl; and

R^(4c) is H, or R^(4c) is C₁₋₆ alkyl, C₁₋₁₂ acyl, aryl, C₃₋₇ cycloalkyl,C₁₋₆ haloalkyl, heterocyclyl, or heteroaryl, wherein each is optionallysubstituted with 1, 2, 3, 4, or 5 substituents selected independentlyfrom the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₄alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl,amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide,halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heterocyclyl, hydroxyl, imino,nitro, sulfonamide and phenyl;

Z is C₁₋₄ alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8substituents selected independently from the group consisting of C₁₋₃alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl, halogen and oxo; orZ is absent;

R¹ is selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₂₋₆ alkynyl and C₃₋₇ cycloalkyl;

R² is selected from the group consisting of H, C₁₋₆ acyl, C₁₋₆ acyloxy,C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl,C₁₋₆ alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₂₋₈dialkylamino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₂₋₈ dialkylcarboxamide, C₂₋₈ dialkylsulfonamide, halogen,C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl, thiol, nitro andsulfonamide;

R³ is selected from the group consisting of H, C₂₋₆ alkenyl, C₁₋₆ alkyl,C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylcarboxamide, halogen, heteroaryl and phenyl; and wherein each ofthe C₂₋₆ alkenyl, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₃₋₇cycloalkyl, heteroaryl and phenyl groups are optionally substituted with1, 2, 3, 4, or 5 substituents selected independently from the groupconsisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,C₁₋₄ alkylthio, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl, nitro and sulfonamide;

R⁵, R⁶ and R⁷ are each selected independently from the group consistingof H, C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl,C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₆ alkylimino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylcarboxamide, C₂₋₈ dialkylsulfonamide, halogen, C₁₋₆ haloalkoxy,C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆haloalkylthio, heterocyclyl, hydroxyl, thiol, and nitro;

and

R⁸ is C₁₋₈-alkyl, aryl, C₃₋₁₀ cycloalkyl, heteroaryl, or heterocyclyleach optionally substituted with substituents selected independentlyfrom the group consisting of C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino,C₁₋₆ alkylimino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₈ dialkylcarboxamide, C₂₋₈dialkylsulfonamide, halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio,heteroaryl, heterocyclyl, hydroxyl, thiol, nitro, phenoxy and phenyl,wherein the C₂₋₆ alkenyl, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₁₋₆ alkylamino,C₁₋₆ alkylimino, C₂₋₈ dialkylamino, heteroaryl, heterocyclyl, phenyl,and phenoxy, and each the substituent is optionally substituted with 1,2, 3, 4, or 5 substituents selected independently from the groupconsisting of C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylcarboxamide,halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, heterocyclyl, hydroxyl, thiol andnitro.

One aspect of the present invention pertains to pharmaceuticalcompositions comprising a compound of the present invention and apharmaceutically acceptable carrier.

One aspect of the present invention pertains to methods for modulatingthe activity of a 5-HT_(2A) serotonin receptor by contacting thereceptor with a compound according to any of the embodiments describedherein or a pharmaceutical composition thereof.

One aspect of the present invention pertains to methods for treating a5-HT_(2A) associated disorder in an individual comprising administeringto the individual in need thereof a therapeutically effective amount ofa compound according to any of the embodiments described herein or apharmaceutical composition thereof.

One aspect of the present invention pertains to methods for treating a5-HT_(2A) serotonin receptor associated disorder in an individualcomprising administering to the individual in need thereof atherapeutically effective amount of a compound according to any of theembodiments described herein wherein R^(4a) is metabolically-labilegroup.

One aspect of the present invention pertains to methods for treating a5-HT_(2A) serotonin receptor associated disorder in an individualcomprising administering to the individual in need thereof atherapeutically effective amount of a prodrug whereby the prodrugundergoes a conversion into a compound according to any of theembodiments described herein wherein R^(4a) is H and the conversiontakes place within the body of the individual.

One aspect of the present invention pertains to processes for preparinga composition comprising admixing a compound according to any of theembodiments described herein and a pharmaceutically acceptable carrier.

One aspect of the present invention pertains to the use of a compound ofthe present invention for the production of a medicament for use in thetreatment of a 5-HT_(2A) associated disorder.

One aspect of the present invention pertains to compounds according toany of the embodiments described herein for use in a method of treatmentof the human or animal body by therapy.

One aspect of the present invention pertains to compounds according toany of the embodiments described herein for use in a method for thetreatment of a 5-HT_(2A) associated disorder, as described herein, inthe human or animal body by therapy.

These and other aspects of the invention disclosed herein will be setforth in greater detail as the patent disclosure proceeds.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the general synthetic scheme for the preparation ofintermediate compounds of the present invention. FIG. 1 shows a generalcoupling method between a pyrazole boronic acid and an aryl triflate, itis understood that similar coupling methods known in the art can also beused, and a halide, such as, I, Br or Cl, can be used in place of thetriflate.

FIG. 2 shows the general synthetic scheme for the preparation ofintermediate compounds of the present invention wherein “V” is oxygen.FIG. 2 shows a general coupling method between a pyrazole boronic acidand a phenyl halide using coupling methods known in the art, such as aSuzuki coupling, and the like. FIG. 2 further shows the use oforthogonal protecting groups for the oxygen (V═O) and the nitrogen.After the coupling reaction the phenol protecting group is removed and avariety of —W-Q groups can be introduced. Subsequently, the alkyl amideprotecting group can be hydrolyzed to provide the amine intermediate ofthe present invention.

FIG. 3 shows the general synthetic scheme for the preparation ofintermediate compounds of the present invention. FIG. 3 illustratesgeneral methods for introducing a variety of halogens to compounds ofthe invention. It is understood that these halogenation reactions canalso be conducted later in the synthesis, for example as the last step.

FIG. 4 shows the general synthetic scheme for the preparation ofintermediate compounds of the present invention. FIG. 4 shows thegeneral reactions, such as, alkylation and Mitsunobu-like reactions, forintroducing the W-Q group.

FIG. 5 shows the general synthetic scheme for the preparation ofcompounds of the present invention. FIG. 5 shows the general couplingreactions of the amino-intermediate with carboxylic acids, acyl halides,and the like.

FIG. 6 shows the general synthetic scheme for the preparation ofintermediates and compounds of the present invention. FIG. 6 illustratesthe general methods for preparing pyrazoles of the present inventionusing substituted and unsubstituted hydrazines.

FIG. 7 shows the general synthetic scheme for the preparation ofcompounds of the invention wherein the —W-Q group is introduced in thelast step(s). FIG. 7 shows the general reactions, such as, alkylationand Mitsunobu-like reactions, for introducing the —W-Q group.

FIG. 8 shows the general synthetic scheme for the preparation ofcompounds of the invention wherein V is NH in Formula (Ia) and the —W-Qgroup is introduced in the last step(s). FIG. 8 shows the generalreactions, such as, alkylation reactions, for introducing the —W-Q groupwherein V is NH.

DEFINITIONS

The scientific literature that has evolved around receptors has adopteda number of terms to refer to ligands having various effects onreceptors. For clarity and consistency, the following definitions willbe used throughout this patent document.

The term “agonists” shall mean moieties that interact and activate thereceptor, such as the 5-HT_(2A) receptor, and initiates a physiologicalor pharmacological response characteristic of that receptor. Forexample, when moieties activate the intracellular response upon bindingto the receptor, or enhance GTP binding to membranes.

The term “antagonist” is intended to mean moieties that competitivelybind to the receptor at the same site as agonists (for example, theendogenous ligand), but which do not activate the intracellular responseinitiated by the active form of the receptor, and can thereby inhibitthe intracellular responses by agonists or partial agonists. Antagonistsdo not diminish the baseline intracellular response in the absence of anagonist or partial agonist.

The term “contact or contacting” is intended to mean bringing theindicated moieties together, whether in an in vitro system or an in vivosystem. Thus, “contacting” a H3 receptor with a compound of theinvention includes the administration of a compound of the presentinvention to an individual, preferably a human, having a H3 receptor, aswell as, for example, introducing a compound of the invention into asample containing a cellular or more purified preparation containing aH3 receptor.

The term “in need of treatment” is intended to mean a judgment made by acaregiver (e.g. physician, nurse, nurse practitioner, etc. in the caseof humans; veterinarian in the case of animals, including non-humanmammals) that an individual or animal requires or will benefit fromtreatment. This judgment is made based on a variety of factors that arein the realm of a caregiver's expertise, but that includes the knowledgethat the individual or animal is ill, or will become ill, as the resultof a disease, condition or disorder that is treatable by the compoundsof the invention. Accordingly, the compounds of the invention can beused in a protective or preventive manner; or compounds of the inventioncan be used to alleviate, inhibit or ameliorate the disease, conditionor disorder.

The term “individual” is intended to mean any animal, including mammals,preferably mice, rats, other rodents, rabbits, dogs, cats, swine,cattle, sheep, horses, or primates, and most preferably humans.

The term “inverse agonists” is intended to mean moieties that bind theendogenous form of the receptor or to the constitutively activated formof the receptor, and which inhibit the baseline intracellular responseinitiated by the active form of the receptor below the normal base levelof activity which is observed in the absence of agonists or partialagonists, or decrease GTP binding to membranes. Preferably, the baselineintracellular response is inhibited in the presence of the inverseagonist by at least 30%, more preferably by at least 50%, and mostpreferably by at least 75%, as compared with the baseline response inthe absence of the inverse agonist.

The term “isolated” refers to material that is removed from its originalenvironment (e.g., the natural environment if it is naturallyoccurring). For example, a metabolite that is formed from a parentcompound present in a natural system (e.g. individual) is not isolated,but the same metabolite, separated from some or all of the coexistingmaterials in the natural system is considered isolated. In addition, themetabolite that is prepared by synthetic means is also consideredisolated.

The term “modulate or modulating” is intended to mean an increase ordecrease in the amount, quality, response or effect of a particularactivity, function or molecule.

The term “metabolically-labile group” as used herein refers to any groupthat, following administration of a compound containing the group to anindividual, is converted in vivo to a compound of Formula (Ia) whereinR^(4a) is H. The conversion of the “metabolically-liable group” can beby metabolic and/or chemical processes and can occur in one step orthrough a series of two or more steps. Representative examples of a“metabolically-labile group” include, but are not limited to,—C(═O)O—R^(4d) (thus, together with the nitrogen forms a carbamate),—C(═O)—R^(4d) (together with the nitrogen forms an amide), and the like,wherein R^(4d) is C₁₋₁₈ alkyl, aryl, arylalkyl, heteroaryl, andheteroarylalkyl each optionally substituted with 1, 2, 3, 4, or 5substituents selected independently from the group consisting of C₁₋₆acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylcarboxamide,C₂₋₈ dialkylsulfonamide, halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl,thiol, nitro, oxo, phenyl, and sulfonamide. In some embodiments, the“metabolically-labile group” is C₁₋₁₂ acyl, carbo-C₁₋₁₂-alkoxy, orC(═O)O-aryl, wherein the C₁₋₁₂ acyl, carbo-C₁₋₁₂-alkoxy, and—C(═O)O-aryl is optionally substituted with 1, 2, 3, 4, or 5substituents selected independently from the group consisting of C₁₋₅acyloxy, C₁₋₆ alkylcarboxamide, amino, C₁₋₆ alkylamino, C₂₋₈dialkylamino, C₁₋₆ alkylimino, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl,C₁₋₆ alkylthio, halogen, nitro, and phenyl. The “metabolically-labilegroups” illustrated are exemplary and are not exhaustive, and oneskilled in the art could prepare other known varieties of groups. Insome cases, a “metabolically-labile group” (i.e., R^(4a)) can serve toimprove efficacy or safety through improved oral bioavailability, orpharmacodynamic half-life, etc.

The term “pharmaceutical composition” is intended to mean a compositioncomprising at least one active ingredient; including but not limited to,salts, solvates and hydrates of compounds of Formula (Ia); whereby thecomposition is amenable to investigation for a specified, efficaciousoutcome in a mammal (for example, without limitation, a human). Those ofordinary skill in the art will understand and appreciate the techniquesappropriate for determining whether an active ingredient has a desiredefficacious outcome based upon the needs of the artisan.

The term “prodrug” as used herein refers to any compound that whenadministered to a biological system (e.g., in vivo in an individual, andthe like) generates a compound of Formula (Ia), wherein R^(4a) is H, asa result of chemical reaction(s), enzyme catalyzed chemical reaction(s),and/or metabolic chemical reaction(s). In some embodiments, compounds ofthe present invention can be converted to “pro-drugs.” In someembodiments, “pro-drugs” refer to compounds that have been modified withspecific chemical groups known in the art and when administered into anindividual these groups undergo biotransformation to give the parentcompound. Pro-drugs can thus be viewed as compounds of the inventioncontaining one or more specialized non-toxic protective groups used in atransient manner to alter or to eliminate a property of the compound. Inone general aspect, the “pro-drug” approach is utilized to facilitateoral absorption. A thorough discussion is provided in T. Higuchi and V.Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S.Symposium Series; and in Bioreversible Carriers in Drug Design, ed.Edward B. Roche, American Pharmaceutical Association and Pergamon Press,1987, both of which are hereby incorporated by reference in theirentirety.

The term “therapeutically effective amount” is intended to mean theamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinician, which includes one or more of the following:

(1) Preventing the disease; for example, preventing a disease, conditionor disorder in an individual that may be predisposed to the disease,condition or disorder but does not yet experience or display thepathology or symptomatology of the disease,

(2) Inhibiting the disease; for example, inhibiting a disease, conditionor disorder in an individual that is experiencing or displaying thepathology or symptomatology of the disease, condition or disorder (i.e.,arresting further development of the pathology and/or symptomatology),and

(3) Ameliorating the disease; for example, ameliorating a disease,condition or disorder in an individual that is experiencing ordisplaying the pathology or symptomatology of the disease, condition ordisorder (i.e., reversing the pathology and/or symptomatology).

Chemical Group, Moiety or Radical:

The term directly preceeding the chemical group beginning with “C”followed directly by a subscript number or a subscript range of numbersrefers to the number of carbons associated with the chemical group. Forexample, the term “C₁₋₆” in the chemical group “C₁₋₆ alkyl” refers to analkyl group containing one, two, three, four, five, or six carbons, andall possible isomers.

The term “C₁₋₁₂ acyl” denotes a C₁₋₁₂ alkyl radical attached to acarbonyl wherein alkyl has the same definition as described herein, someembodiments are when acyl is C₁₋₆ acyl, some embodiments are when acylis C₁₋₅ acyl; some examples include, but are not limited to, acetyl,propionyl, n-butanoyl, iso-butanoyl, sec-butanoyl, t-butanoyl (i.e.,pivaloyl), pentanoyl and the like.

The term “C₁₋₁₂ acyloxy” denotes an acyl radical attached to an oxygenatom wherein acyl has the same definition has described herein; someembodiments are when acyloxy is C₁₋₁₁ acyloxy, some embodiments are whenacyloxy is C₁₋₁₀ acyloxy, some embodiments are when acyloxy is C₁₋₈acyloxy, some embodiments are when acyloxy is C₁₋₆ acyloxy, someembodiments are when acyloxy is C₁₋₅ acyloxy, some embodiments are whenacyloxy is C₁₋₄ acyloxy, some embodiments are when acyloxy is C₁₀₋₁₂acyloxy, some embodiments are when acyloxy is C₈₋₁₀ acyloxy. Someexamples include, but are not limited to, acetyloxy, propionyloxy,butanoyloxy, iso-butanoyloxy, sec-butanoyloxy, t-butanoyloxy,pentanoyloxy, hexanoyloxy, heptanoyloxy, octanoyloxy, nonanoyloxy,decanoyloxy, undecanoyloxy, dodecanoyloxy, and the like.

The term “C₂₋₆ alkenyl” denotes a radical containing 2 to 6 carbonswherein at least one carbon-carbon double bond is present, someembodiments are 2 to 4 carbons, some embodiments are 2 to 3 carbons, andsome embodiments have 2 carbons. Both E and Z isomers are embraced bythe term “alkenyl.” Furthermore, the term “alkenyl” includes di- andtri-alkenyls. Accordingly, if more than one double bond is present thenthe bonds may be all E or Z or a mixtures of E and Z. Examples of analkenyl include vinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexanyl,2,4-hexadienyl and the like.

The term “C₁₋₆ alkoxy” as used herein denotes an alkyl radical, asdefined herein, attached directly to an oxygen atom. Examples includemethoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy,sec-butoxy and the like.

The term “C₁₋₆ alkoxycarbonylamino” denotes the group represented by theformula:

wherein C₁₋₆ alkyl has the same definition as found herein. Examples ofC₁₋₆ alkoxycarbonylamino include methoxycarbonylamino,ethoxycarbonylamino, isopropoxycarbonylamino, propoxycarbonylamino,tert-butoxycarbonylamino, butoxycarbonylamino, and the like.

The term “C₁₋₈ alkyl” denotes a straight or branched carbon radicalcontaining 1 to 8 carbons, some embodiments are 1 to 6 carbons, someembodiments are 1 to 4 carbons, some embodiments are 1 to 3 carbons, andsome embodiments are 1 or 2 carbons. Examples of an alkyl include, butare not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl,sec-butyl, iso-butyl, t-butyl, pentyl, iso-pentyl, t-pentyl, neo-pentyl,1-methylbutyl [i.e., —CH(CH₃)CH₂CH₂CH₃], 2-methylbutyl [i.e.,—CH₂CH(CH₃)CH₂CH₃], n-hexyl and the like.

The term “C₁₋₆ alkylcarboxamido” or “C₁₋₆ alkylcarboxamide” denotes asingle C₁₋₆ alkyl group attached to the nitrogen of an amide group,wherein alkyl has the same definition as found herein. The C₁₋₆alkylcarboxamido may be represented by the following:

Examples include, but are not limited to, N-methylcarboxamide,N-ethylcarboxamide, N-n-propylcarboxamide, N-iso-propylcarboxamide,N-n-butylcarboxamide, N-sec-butylcarboxamide, N-iso-butylcarboxamide,N-t-butylcarboxamide and the like.

The term “C₁₋₄ alkylene” refers to a C₁₋₄ divalent straight carbon groupcontaining 1 to 4 carbons, some embodiments are 1 to 3 carbons, someembodiments are 1 to 2 carbons. In some embodiments alkylene refers to,for example, —CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and the like.

The term “C₁₋₆ alkylsulfinyl” denotes a C₁₋₆ alkyl radical attached to asulfoxide radical of the formula: —S(O)— wherein the alkyl radical hasthe same definition as described herein. Examples include, but are notlimited to, methylsulfinyl, ethylsulfinyl, n-propylsulfinyl,iso-propylsulfinyl, n-butylsulfinyl, sec-butylsulfinyl,iso-butylsulfinyl, t-butylsulfinyl, and the like.

The term “C₁₋₆ alkylsulfonamide” refers to the groups shown below:

wherein C₁₋₆ alkyl has the same definition as described herein.

The term “C₁₋₆ alkylsulfonyl” denotes a C₁₋₆ alkyl radical attached to asulfone radical of the formula: —S(O)₂—wherein the alkyl radical has thesame definition as described herein. Examples include, but are notlimited to, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl,iso-propylsulfonyl, n-butylsulfonyl, sec-butylsulfonyl,iso-butylsulfonyl, t-butylsulfonyl, and the like.

The term “C₁₋₆ alkylthio” denotes a C₁₋₆ alkyl radical attached to asulfide of the formula: —S— wherein the alkyl radical has the samedefinition as described herein. Examples include, but are not limitedto, methylsulfanyl (i.e., CH₃S—), ethylsulfanyl, n-propylsulfanyl,iso-propylsulfanyl, n-butylsulfanyl, sec-butylsulfanyl,iso-butylsulfanyl, t-butylsulfanyl, and the like.

The term “C₁₋₆ alkylthiocarboxamide” denotes a thioamide of thefollowing formulae:

wherein C₁₋₄ alkyl has the same definition as described herein.

The term “C₁₋₆ alkylureyl” denotes the group of the formula: —NC(O)N—wherein one or both of the nitrogens are substituted with the same ordifferent C₁₋₆ alkyl group wherein alkyl has the same definition asdescribed herein. Examples of an alkylureyl include, but are not limitedto, CH₃NHC(O)NH—, NH₂C(O)NCH₃—, (CH₃)₂NC(O)NH—, (CH₃)₂NC(O)NH—,(CH₃)₂NC(O)NCH₃—, CH₃CH₂NHC(O)NH—, CH₃CH₂NHC(O)NCH₃—, and the like.

The term “C₂₋₆ alkynyl” denotes a radical containing 2 to 6 carbons andat least one carbon-carbon triple bond, some embodiments are 2 to 4carbons, some embodiments are 2 to 3 carbons, and some embodiments have2 carbons. Examples of an alkynyl include, but are not limited to,ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl,1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl,3-hexynyl, 4-hexynyl, 5-hexynyl and the like. The term “alkynyl”includes di- and tri-ynes.

The term “amino” denotes the group —NH₂.

The term “C₁₋₆ alkylamino” denotes one alkyl radical attached to anamino radical wherein the alkyl radical has the same meaning asdescribed herein. Some examples include, but are not limited to,methylamino, ethylamino, n-propylamino, iso-propylamino, n-butylamino,sec-butylamino, iso-butylamino, t-butylamino, and the like. Someembodiments are “C₁₋₂ alkylamino.”

The term “aryl” denotes a 6- to 12-membered mono- or bicyclic ringsystem containing only ring carbons wherein at least one ring isaromatic. Examples include phenyl, 1,2,3,4-tetrahydro-naphthalen-1-yl,1,2,3,4-tetrahydro-naphthalen-2-yl, 5,6,7,8-tetrahydro-naphthalen-1-yl,5,6,7,8-tetrahydro-naphthalen-2-yl, indan-4-yl, naphtha-1-yl,naphtha-2-yl, and the like.

The term “arylalkyl” defines a C₁-C₄ alkylene, such as —CH₂—, —CH₂CH₂—and the like, which is further substituted with an aryl group. Examplesof an “arylalkyl” include benzyl, phenethylene and the like.

The term “arylcarboxamido” denotes a single aryl group attached to thenitrogen of an amide group, wherein aryl has the same definition asfound herein. The example is N-phenylcarboxamide.

The term “arylureyl” denotes the group —NC(O)N— where one of thenitrogens are substituted with an aryl.

The term “benzyl” denotes the group —CH₂C₆H₅.

The term “bicyclic” refers to two C₄₋₇ cyclalkyl groups that share tworing carbons thus forming either a fused or bridged ring. Bicyclicexamples include, but not limited to, bicyclo[1.1.1]pentyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, and the like.

The term “carbo-C₁₋₆-alkoxy” refers to a C₁₋₆ alkyl ester of acarboxylic acid, wherein the alkyl group is as defined herein. Examplesinclude, but are not limited to, carbomethoxy, carboethoxy,carbopropoxy, carboisopropoxy, carbobutoxy, carbo-sec-butoxy,carbo-iso-butoxy, carbo-t-butoxy, carbo-n-pentoxy, carbo-iso-pentoxy,carbo-t-pentoxy, carbo-neo-pentoxy, carbo-n-hexyloxy, and the like.

The term “carboxamide” refers to the group —CONH₂.

The term “carboxy” or “carboxyl” denotes the group —CO₂H; also referredto as a carboxylic acid group.

The term “cyano” denotes the group —CN.

The term “C₄₋₇ cycloalkenyl” denotes a non-aromatic ring radicalcontaining 4 to 7 ring carbons and at least one double bond; someembodiments contain 4 to 6 carbons; some embodiments contain 4 to 5carbons; some embodiments contain 4 carbons. Examples includecyclobutenyl, cyclopentenyl, cyclopentenyl, cyclohexenyl, and the like.

The term “C₃₋₁₀ cycloalkyl” denotes a saturated monocyclic, bicyclic, ortricyclic ring radical containing 3 to 8 carbons; some embodimentscontain 3 to 7 carbons; some embodiments contain 3 to 6 carbons; someembodiments contain 3 to 5 carbons; some embodiments contain 5 to 7carbons; some embodiments contain 3 to 4 carbons. Examples includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,adamantyl, bicyclo[2.2.1]heptyl, and the like.

The term “C₃₋₇ cycloalkylcarbonyl” denotes a C₃₋₇ cycloalkyl group, asdescribed herein, bonded to the carbon of a carbonyl group (i.e.,—C(═O)—). Examples of the C₃₋₇ cycloalkylcarbonyl group include, but notlimited to, cyclopropylcarbonyl, cyclobutylcarbonyl,cyclopentylcarbonyl, and the like.

The term “C₃₋₆ cycloalkylene” refers to a divalent cycloalkyl radical,where cycloalkyl is as defined herein, containing 3 to 6 carbons; someembodiments contain 3 to 5 carbons; some embodiments contain 3 to 4carbons. In some embodiments, the C₃₋₆ cycloalkylene group has the twobonding groups on the same ring carbon, for example:

In some embodiments, the C₃₋₆ cycloalkylene group has the two bondinggroups on different ring carbons. It is understood that when the twogroups of the C₃₋₆ cycloalkylene group are on different ring carbonsthey may be cis or trans or mixtures thereof with respect to each other.

The term “C₂₋₈ dialkylamino” denotes an amino substituted with two ofthe same or different C₁₋₄ alkyl radicals wherein alkyl radical has thesame definition as described herein. Some examples include, but are notlimited to, dimethylamino, methylethylamino, diethylamino,methylpropylamino, methylisopropylamino, ethylpropylamino,ethylisopropylamino, dipropylamino, propylisopropylamino and the like.Some embodiments are “C₂₋₄ dialkylamino.”

The term “C₂₋₈ dialkylcarboxamido” or “C₂₋₈ dialkylcarboxamide” denotestwo alkyl radicals, that are the same or different, attached to an amidegroup, wherein alkyl has the same definition as described herein. A C₂₋₈dialkylcarboxamido may be represented by the following groups:

wherein C₁₋₄ has the same definition as described herein. Examples of adialkylcarboxamide include, but are not limited to,N,N-dimethylcarboxamide, N-methyl-N-ethylcarboxamide,N,N-diethylcarboxamide, N-methyl-N-isopropylcarboxamide, and the like.

The term “C₂₋₈ dialkylsulfonamide” refers to one of the following groupsshown below:

wherein C₁₋₄ has the same definition as described herein, for examplebut are not limited to, methyl, ethyl, n-propyl, isopropyl, and thelike.

The term “C₂₋₈ dialkylthiocarboxamido” or “C₂₋₈ dialkylthiocarbox-amide”denotes two alkyl radicals, that are the same or different, attached toa thioamide group, wherein alkyl has the same definition as describedherein. A C₂₋₈ dialkylthiocarboxamido or C₂₋₈ dialkylthiocarboxamide maybe represented by the following groups:

Examples of a dialkylthiocarboxamide include, but are not limited to,N,N-dimethylthiocarboxamide, N-methyl-N-ethylthiocarboxamide and thelike.

The term “formyl” refers to the group —CHO.

The term “C₁₋₆ haloalkoxy” denotes a C₁₋₆ haloalkyl, as defined herein,which is directly attached to an oxygen atom. Examples include, but arenot limited to, difluoromethoxy, trifluoromethoxy,2,2,2-trifluoroethoxy, pentafluoroethoxy and the like.

The term “C₁₋₆ haloalkyl” denotes an C₁₋₆ alkyl group, defined herein,wherein the alkyl is substituted with one halogen up to fullysubstituted and a fully substituted C₁₋₆ haloalkyl can be represented bythe formula C_(n)L_(2n+1) wherein L is a halogen and “n” is 1, 2, 3, 4,5 or 6; when more than one halogen is present then they may be the sameor different and selected from the group consisting of F, Cl, Br and I,preferably F. Examples of haloalkyl groups include, but are not limitedto, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl,2,2,2-trifluoroethyl, pentafluoroethyl and the like.

The term “C₁₋₆ haloalkylcarboxamide” denotes an C₁₋₆ alkylcarboxamidegroup, defined herein, wherein the alkyl is substituted with one halogenup to fully substituted represented by the formula C_(n)L_(2n+1) whereinL is a halogen and “n” is 1, 2, 3, 4, 5 or 6. When more than one halogenis present they may be the same or different and selected from the groupconsisting of F, Cl, Br and I, preferably F.

The term “C₁₋₆ haloalkylsulfinyl” denotes a C₁₋₆ haloalkyl radicalattached to a sulfoxide group of the formula: —S(O)— wherein thehaloalkyl radical has the same definition as described herein. Examplesinclude, but are not limited to, trifluoromethylsulfinyl,2,2,2-trifluoroethylsulfinyl, 2,2-difluoroethylsulfinyl and the like.

The term “C₁₋₆ haloalkylsulfonyl” denotes a C₁₋₆ haloalkyl radicalattached to a sulfone group of the formula: —S(O)₂— wherein haloalkylhas the same definition as described herein. Examples include, but arenot limited to, trifluoromethylsulfonyl, 2,2,2-trifluoroethylsulfonyl,2,2-difluoroethylsulfonyl and the like.

The term “C₁₋₆ haloalkylthio” denotes a C₁₋₆ haloalkyl radical directlyattached to a sulfur wherein the haloalkyl has the same meaning asdescribed herein. Examples include, but are not limited to,trifluoromethylthio (i.e., CF₃S—, also referred to astrifluoromethylsulfanyl), 1,1-difluoroethylthio,2,2,2-trifluoroethylthio and the like. The term “halogen” or “halo”denotes to a fluoro, chloro, bromo or iodo group.

The term “heteroaryl” denotes a 6- to 12-membered mono- or bicyclic ringsystem wherein at least one ring atom is a heteroatom and at least onering is aromatic. Examples of a heteroatom include, O, S, N and thelike. In some embodiments, N is optionally substituted, for example, H,or C₁₋₄ alkyl. Examples of heteroaryl groups include, but are notlimited to, pyridyl, benzofuranyl, pyrazinyl, pyridazinyl, pyrimidinyl,triazinyl, quinolinyl, benzoxazolyl, benzothiazolyl, 1H-benzimidazolyl,isoquinolinyl, quinazolinyl, quinoxalinyl, pyrrolyl, indolyl,1H-benzoimidazol-2-yl, benzo[1,3]dioxol-5-yl,3,4-dihydro-2H-benzo[1,4]oxazin-7-yl, 2,3-dihydro-benzofurn-7-yl,2,3-dihydro-indol-1-yl, and the like. Other examples include, but arenot limited to, those in TABLE 1, TABLE 2, and the like.

The term “heterobicyclic” denotes a non-aromatic bicyclic ring, asdescribed herein, wherein 1, 2, or 3 ring carbons are replaced with aheteroatom selected from, but are not limited to, the group consistingof O, S, S(═O), S(═O)₂, and NH, wherein the nitrogen can be optionallysubstituted, and 1 or 2 ring carbons can be optionally substituted withoxo or thiooxo thus together form a carbonyl or thiocarbonyl grouprespectively. Examples of a heterobicyclic group include, but are notlimited to, 2,5-diaza-bicyclo[2.2.1]hept-2-yl,7-aza-bicyclo[2.2.1]hept-7-yl, and the like.

The term “heterocyclic” denotes a 3- to 12-membered mono- or bicyclicnon-aromatic ring system wherein at least one ring atom is a heteroatom.In some embodiments, heteroatom is selected from, but are not limitedto, the group consisting of O, S, S(═O), S(═O)₂, NH, wherein the N ofthe heterocyclic can be optionally substituted as described herein, insome embodiments, the nitrogen is optionally substituted with C₁₋₄ acylor C₁₋₄ alkyl, and ring carbon atoms optionally substituted with oxo ora thiooxo thus forming a carbonyl or thiocarbonyl group. Theheterocyclic group can be bonded at any available ring atom, forexample, ring carbon, ring nitrogen, and the like. In some embodiments,the heterocyclic group is a 3-, 4-, 5-, 6- or 7-membered containingring. Examples of a heterocyclic group include, but are not limited to,aziridin-1-yl, aziridin-2-yl, azetidin-1-yl, azetidin-2-yl,azetidin-3-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl,piperidin-4-yl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl,piperzin-1-yl, piperzin-2-yl, piperzin-3-yl, piperzin-4-yl,pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, [1,3]-dioxolan-2-yl,thiomorpholin-4-yl, [1,4]oxazepan-4-yl,1,1-dioxo-1λ⁶-thiomorpholin-4-yl, azepan-1-yl, azepan-2-yl, azepan-3-yl,azepan-4-yl, octahydro-quinolin-1-yl, octahydro-isoquinolin-2-yl, andthe like.

The term “hydroxyl” refers to the group —OH.

The term “nitro” refers to the group —NO₂.

As used herein, the term “oxo” refers to the substituent ═O,accordingly, when a carbon is substituted by an oxo group the new groupresulting from the carbon and oxo together is a carbonyl group.

The term “phenoxy” refers to the group C₆H₅O—.

The term “phenyl” refers to the group C₆H₅—.

The term“sulfonic acid” refers to the group —SO₃H.

The term “thiol” denotes the group —SH.

COMPOUNDS OF THE INVENTION

One aspect of the present invention pertains to certain compounds asshown in Formula (Ia):

or a pharmaceutically acceptable salt, hydrate or solvate thereof;wherein R¹, R², R³, R⁵, R⁶, R⁷, R⁸, V, W, Q, and Z have the samedefinitions as described herein, supra and infra.

One aspect of the present invention pertains to certain compounds asshown in Formula (Ia) wherein:

R^(4a) is H, C₁₋₁₂ acyl, carbo-C₁₋₁₂-alkoxy, or C(═O)O-aryl, wherein theC₁₋₁₂ acyl, carbo-C₁₋₁₂-alkoxy, and —C(═O)O-aryl is optionallysubstituted with 1, 2, 3, 4, or 5 substituents selected independentlyfrom the group consisting of C₁₋₅ acyloxy, C₁₋₆ alkylcarboxamide, amino,C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₆ alkylimino, C₁₋₆ alkylsulfinyl,C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, halogen, nitro, and phenyl.

In some embodiments, the present invention pertains to compounds ofFormula (Ia), as described herein, that are isolated.

In some embodiments, the present invention pertains to compounds ofFormula (Ia), as described herein, that are isolated outside the body ofan individual.

In some embodiments, the present invention pertains to compounds ofFormula (Ia), as described herein, that are isolated outside the body ofan individual. In some embodiments, isolated compounds of Formula (Ia)have a purity of greater than about 0.1%, about 1%, about 5%, about 10%,about 15%, about 20%, about 25%, about 30%, about 40%, about 45%, about50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,about 85%, about 90%, about 95%, about 98%, or about 99%.

In some embodiments, the present invention pertains to compounds ofFormula (Ia), as described herein, or a pharmaceutically acceptablesalt, hydrate, solvate, or N-oxide thereof.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables (e.g.,R¹, R², R³, R⁵, R⁶, R⁷, R⁸, V, W, Q, Z, etc.) contained within thegeneric chemical formulae described herein [e.g. (Ia), (Ic), (Ie), etc.]are specifically embraced by the present invention just as if they wereexplicitly disclosed, to the extent that such combinations embracecompounds that result in stable compounds (ie., compounds that can beisolated, characterized and tested for biological activity). Inaddition, all subcombinations of the chemical groups listed in theembodiments describing such variables, as well as all subcombinations ofuses and medical indications described herein, are also specificallyembraced by the present invention just as if each of such subcombinationof chemical groups and subcombination of uses and medical indicationswere explicitly disclosed herein.

As used herein, “substituted” indicates that at least one hydrogen atomof the chemical group is replaced by a non-hydrogen substituent orgroup, the non-hydrogen substituent or group can be monovalent ordivalent. When the substituent or group is divalent, then it isunderstood that this group is further substituted with anothersubstituent or group. When a chemical group herein is “substituted” itmay have up to the full valance of substitution; for example, a methylgroup can be substituted by 1, 2, or 3 substituents, a methylene groupcan be substituted by 1 or 2 substituents, a phenyl group can besubstituted by 1, 2, 3, 4, or 5 substituents, a naphthyl group can besubstituted by 1, 2, 3, 4, 5, 6, or 7 substituents and the like.Likewise, “substituted with one or more substituents” refers to thesubstitution of a group with one substituent up to the total number ofsubstituents physically allowed by the group. Further, when a group issubstituted with more than one group they can be identical or they canbe different.

Compounds of the invention can also include tautomeric forms, such asketo-enol tautomers, and the like. Tautomeric forms can be inequilibrium or sterically locked into one form by appropriatesubstitution. It is understood that the various tautomeric forms arewithin the scope of the compounds of the present invention.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates and/or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include deuterium and tritium.

It is understood and appreciated that compounds of the present inventionmay have one or more chiral centers, and therefore can exist asenantiomers and/or diastereomers. The invention is understood to extendto and embrace all such enantiomers, diastereomers and mixtures thereof,including but not limited, to racemates. Accordingly, some embodimentsof the present invention pertain to compounds of the present inventionthat are R enantiomers. Further, some embodiments of the presentinvention pertain to compounds of the present invention that are Senantiomers. In examples where more than one chiral center is present,then, some embodiments of the present invention include compounds thatare RS or SR enantiomers. In further embodiments, compounds of thepresent invention are RR or SS enantiomers. It is understood thatcompounds of the present invention are intended to represent allpossible individual enantiomers and mixtures thereof just as if each hadbeen individually named with the structure provided, unless stated orshown otherwise.

Some embodiments of the present invention pertain to certain compoundsas shown in the following Formula (Ic):

wherein each variable in Formula (Ic) has the same meaning as describedherein, supra and infra.

Some embodiments of the present invention pertain to certain compoundsas shown in Formula (Ie):

wherein each variable in Formula (Ie) has the same meaning as describedherein, supra and infra.

In some embodiments, V is O.

Some embodiments of the present invention pertain to certain compoundsas shown in Formula (Ig):

wherein each variable in Formula (Ig) has the same meaning as describedherein, supra and infra.

In some embodiments, W is —CH₂CH₂— optionally substituted with 1 to 2substituents selected independently from the group consisting of C₁₋₃alkyl and oxo.

In some embodiments, W is —CH₂CH₂—, —CH₂C(CH₃)₂—, or —CH₂C(═O)—.

In some embodiments, W is —CH₂CH₂—.

Some embodiments of the present invention pertain to certain compoundsas shown in Formula (Ii):

wherein each variable in Formula (Ii) has the same meaning as describedherein, supra and infra.

In some embodiments, Z is absent.

Some embodiments of the present invention pertain to certain compoundsas shown in Formula (Ik):

wherein each variable in Formula (Ik) has the same meaning as describedherein, supra and infra.

In some embodiments, Z is —CH₂— or —CH₂CH₂—.

In some embodiments, R¹ is C₁₋₆ alkyl.

In some embodiments, R¹ is —CH₃.

In some embodiments, R₁ is H.

It is understood when R₁ is H that tautomers are possible. It is wellunderstood and appreciated in the art that pyrazoles can exist invarious tautomeric forms. Two possible tautomeric forms are illustratedbelow:

It is further understood that tautomeric forms can also havecorresponding nomenclature for each represented tautomer, for example,the pyrazol-3-yl groups in Formula (Im) and Formula (In) can berepresented by the general chemical names 1H-pyrazol-3-yl and2H-pyrazol-3-yl respectively. Therefore, the present invention includesall tautomers and the various nomenclature designations.

In some embodiments, R² is H.

In some embodiments, R³ is H or halogen.

In some embodiments, R³ is H, Cl, or Br.

In some embodiments, Q is —NR^(4a)R^(4b).

Some embodiments of the present invention pertain to certain compoundsas shown in Formula (Ip):

wherein each variable in Formula (Ip) has the same meaning as describedherein, supra and infra.

In some embodiments, R^(4a) is H,

Some embodiments of the present invention pertain to certain compoundsas shown in Formula (Ir):

wherein each variable in Formula (Ir) has the same meaning as describedherein, supra and infra.

In some embodiments, R^(4a) is C₁₋₁₂ acyl, or carbo-C₁₋₁₂-alkoxy eachoptionally substituted with 1, 2, 3, 4, or 5 substituents selectedindependently from the group consisting of C₁₋₅ acyloxy, C₁₋₆alkylcarboxamide, amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₆alkylimino, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio,halogen, nitro, and phenyl.

In some embodiments, R^(4b) is C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆haloalkyl, heterocyclyl, or heteroaryl, and each is optionallysubstituted with 1, 2, 3, 4, or 5 substituents selected independentlyfrom the group consisting of C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylsulfonyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, cyano, hydroxyl,imino, and phenyl.

In some embodiments,

R^(4a) is H; and

R^(4b) is C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ haloalkyl, heterocyclyl, orheteroaryl, wherein each is optionally substituted with 1, 2, 3, 4, or 5substituents selected independently from the group consisting of C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylsulfonyl, amino, carbo-C₁₋₆-alkoxy,carboxamide, cyano, hydroxyl, imino, and phenyl.

In some embodiments,

R^(4a) is H; and

R^(4b) is C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆ haloalkyl, heterocyclyl, orheteroaryl, wherein each is optionally substituted with 1, 2, 3, 4, or 5substituents selected independently from the group consisting of —OCH₃,—OCH₂CH₃, —CH₃, —S(═O)₂CH₃, amino, —C(═O)OC(CH₃)₃, —C(═O)OCH₂CH₃,—C(═O)NH₂, cyano, hydroxyl, imino, and phenyl.

In some embodiments, Q is selected from the group consisting of—NHCH₂CH₂CF₃, —NHCH₂CH₂OH, —NHCH₂CH₂S(═O)₂CH₃, —NHCH₂CH₃, —NHCH₂CF₂CH₃,—NHCH₂CH₂OOCH₃, —NHCH₂CH₂CN, —NHC(CH₃)₂CH₂CH₃,—NH-tetrahydro-pyran-4-yl, tetrahydro-pyran-4-ylamino, —NHC(═NH)CH₃,piperidin-4-ylamino, 1-tert-butoxycarbonyl-piperidin-4-ylamino,—NHCH₂CH₂CH₂CH₃, 1-methyl-piperidin-4-ylamino, —NHCH₂C(═O)NH₂,—NHCH(CH₃)₂, —NHCH₂CN, —NH-benzyl, —NHCH₂CH₂F,1-ethoxycarbonyl-piperidin-4-ylamino, 1H-[1,2,4]triazol-3-ylamino,—NHC(═NH)NH₂, —NH-cyclopropyl, thiazol-2-ylamino,6-oxo-piperidin-3-ylamino, 1H-tetrazol-5-ylamino, —NHCH₂CH₂OCH₂CH₃,—NHCH₂CH₂OCH(CH₃)₂, —NHC(CH₃)₃, —NHCH₂CH₂CH₃, —NHCH(CH₃)₂, and—NHCH₂CH₂CH₂CN.

In some embodiments, Q is —OR^(4c).

Some embodiments of the present invention pertain to certain compoundsas shown in Formula (It):

wherein each variable in Formula (It) has the same meaning as describedherein, supra and infra.

In some embodiments, R^(4c) is H.

In some embodiments, R^(4c) is C₁₋₆ alkyl, C₁₋₁₂ acyl, aryl, C₃₋₇cycloalkyl, C₁₋₆ haloalkyl, heterocyclyl, or heteroaryl, wherein each isoptionally substituted with 1, 2, 3, 4, or 5 substituents selectedindependently from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₆ alkylamino, C₂₋₈ dialkylamino,C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl,amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide,halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heterocyclyl, hydroxyl, imino,nitro, sulfonamide and phenyl.

In some embodiments, R^(4c) is C₁₋₆ alkyl, C₁₋₁₂ acyl, heterocyclyl, orheteroaryl each optionally substituted with 1 to 2 substituents selectedindependently from the group consisting of C₁₋₈ alkyl, C₂₋₈dialkylamino, and heterocyclyl.

In some embodiments, Q is —OH, —OCH₃, —OC(═O)CH₂-morpholin-4-yl,—OC(═O)CH₂N(CH₃)₂, —OC(═O)CH₂-pyrrolidin-1-yl, or1-methyl-piperidin-4-yloxy.

In some embodiments, R⁵ is H.

In some embodiments, R⁶ is H.

In some embodiments, R⁷ is H.

In some embodiments, R⁵, R⁶ and R⁷ are each H.

In some embodiments, R⁸ is aryl, C₃₋₁₀ cycloalkyl, or heteroaryl eachoptionally substituted with substituents selected independently from thegroup consisting of C₁₋₆ alkoxy, C₁₋₆ alkyl, cyano, halogen, C₁₋₆haloalkoxy, and C₁₋₆ haloalkyl.

In some embodiments, R⁸ is phenyl, cyclopropyl, or heteroaryl eachoptionally substituted with substituents selected independently from thegroup consisting of C₁₋₆ alkoxy, C₁₋₆ alkyl, cyano, halogen, C₁₋₆haloalkoxy, and C₁₋₆ haloalkyl.

In some embodiments, R⁸ is phenyl, cyclopropyl, or isoxazolyl eachoptionally substituted with substituents selected independently from thegroup consisting of C₁₋₆ alkoxy, C₁₋₆ alkyl, cyano, halogen, C₁₋₆haloalkoxy, and C₁₋₆ haloalkyl.

In some embodiments, R⁸ is phenyl, cyclopropyl, or isoxazolyl and eachoptionally substituted with substituents selected independently from thegroup consisting of —CH₃, Br, CF₃, —OCH₃, Cl, F, —OCF₃, and cyano.

In some embodiments, R⁸ is selected from the group consisting of5-methyl-isoxazol-4-yl, 3-bromo-phenyl, 3-trifluoromethyl-phenyl,3-methoxy-phenyl, 4-chloro-phenyl, 3-chloro-phenyl, 2-chloro-phenyl,4-fluoro-phenyl, 2,4-difluoro-phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl,phenyl, 2-methoxy-phenyl, 4-trifluoromethoxy-phenyl,3-trifluoromethoxy-phenyl, 2-fluoro-4-methoxy-phenyl,2-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 4-bromo-phenyl,3-cyano-phenyl, and cyclopropyl.

In some embodiments, R⁸ is heteroaryl.

In some embodiments, heteroaryl is a 5-membered heteroaryl, for example,a 5-membered heteroaryl as shown in TABLE 1:

TABLE 1

wherein the 5-membered heteroaryl is bonded at any available position ofthe ring, for example, a imidazolyl ring can be bonded at one of thering nitrogens (i.e., imidazol-1-yl group) or at one of the ring carbons(i.e., imidazol-2-yl, imidazol-4-yl or imiadazol-5-yl group).

In some embodiments, heteroaryl is a 6-membered heteroaryl, for example,a 6-membered heteroaryl as shown in TABLE 2:

TABLE 2

wherein the heteroaryl group is bonded at any ring carbon.

Some embodiments of the present invention pertain to certain compoundsof Formula (IIa):

wherein:

W is —CH₂CH₂— optionally substituted with 1 to 2 substituents selectedindependently from the group consisting of C₁₋₃ alkyl and oxo;

Q is selected from the group consisting of —NHCH₂CH₂CF₃, —NHCH₂CH₂OH,—NHCH₂CH₂S(═O)₂CH₃, —NHCH₂CH₃, —NHCH₂CF₂CH₃, —NHCH₂CH₂OCH₃, —NHCH₂CH₂CN,—NHC(CH₃)₂CH₂CH₃, —NH-tetrahydro-pyran-4-yl, tetrahydro-pyran-4-ylamino,—NHC(═NH)CH₃, piperidin-4-ylamino,1-tert-butoxycarbonyl-piperidin-4-ylamino, —NHCH₂CH₂CH₂CH₃,1-methyl-piperidin-4-ylamino, —NHCH₂C(═O)NH₂, —NHCH(CH₃)₂, —NHCH₂CN,—NH-benzyl, —NHCH₂CH₂F, 1-ethoxycarbonyl-piperidin-4-ylamino,1H-[1,2,4]triazol-3-ylamino, —NHC(═NH)NH₂, —NH-cyclopropyl,thiazol-2-ylamino, 6-oxo-piperidin-3-ylamino, 1H-tetrazol-5-ylamino,—NHCH₂CH₂OCH₂CH₃, —NHCH₂CH₂OCH(CH₃)₂, —NHC(CH₃)₃, —NHCH₂CH₂CH₃,—NHCH(CH₃)₂, and —NHCH₂CH₂CH₂CN;

R¹ is C₁₋₆ alkyl;

R³ is H or halogen; and

R⁸ is selected from the group consisting of 5-methyl-isoxazol-4-yl,3-bromo-phenyl, 3-trifluoromethyl-phenyl, 3-methoxy-phenyl,4-chloro-phenyl, 3-chloro-phenyl, 2-chloro-phenyl, 4-fluoro-phenyl,2,4-difluoro-phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, phenyl,2-methoxy-phenyl, 4-trifluoromethoxy-phenyl, 3-trifluoromethoxy-phenyl,2-fluoro-4-methoxy-phenyl, 2-trifluoromethyl-phenyl,4-trifluoromethyl-phenyl, 4-bromo-phenyl, 3-cyano-phenyl, andcyclopropyl.

Some embodiments of the present invention pertain to certain compoundsof Formula (IIa) wherein:

wherein:

W is —CH₂CH₂—;

Q is selected from the group consisting of —NHCH₂CH₂CF₃, —NHCH₂CH₂OH,—NHCH₂CH₂S(═O)₂CH₃, —NHCH₂CH₃, —NHCH₂CF₂CH₃, —NHCH₂CH₂OCH₃, —NHCH₂CH₂CN,—NHC(CH₃)₂CH₂CH₃, —NH-tetrahydro-pyran-4-yl, tetrahydro-pyran-4-ylamino,—NHC(═NH)CH₃, piperidin-4-ylamino,1-tert-butoxycarbonyl-piperidin-4-ylamino, —NHCH₂CH₂CH₂CH₃,1-methyl-piperidin-4-ylamino, —NHCH₂C(═O)NH₂, —NHCH(CH₃)₂, —NHCH₂CN,—NH-benzyl, —NHCH₂CH₂F, 1-ethoxycarbonyl-piperidin-4-ylamino,1H-[1,2,4]triazol-3-ylamino, —NHC(═NH)NH₂, —NH-cyclopropyl,thiazol-2-ylamino, 6-oxo-piperidin-3-ylamino, 1H-tetrazol-5-ylamino,—NHCH₂CH₂OCH₂CH₃, —NHCH₂CH₂OCH(CH₃)₂, —NHC(CH₃)₃, —NHCH₂CH₂CH₃,—NHCH(CH₃)₂, and —NHCH₂CH₂CH₂CN;

R¹ is —CH₃;

R³ is H, or Cl; and

R⁸ is selected from the group consisting of 5-methyl-isoxazol-4-yl,3-bromo-phenyl, 3-trifluoromethyl-phenyl, 3-methoxy-phenyl,4-chloro-phenyl, 3-chloro-phenyl, 2-chloro-phenyl, 4-fluoro-phenyl,2,4-difluoro-phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, phenyl,2-methoxy-phenyl, 4-trifluoromethoxy-phenyl, 3-trifluoromethoxy-phenyl,2-fluoro-4-methoxy-phenyl, 2-trifluoromethyl-phenyl,4-trifluoromethyl-phenyl, 4-bromo-phenyl, 3-cyano-phenyl, andcyclopropyl.

Some embodiments of the present invention pertain to certain compoundsof Formula (IIa) wherein:

wherein:

W is —CH₂CH₂— optionally substituted with 1 to 2 substituents selectedindependently from the group consisting of C₁₋₃ alkyl and oxo;

Q is —OH, —OCH₃, —OC(═O)CH₂-morpholin-4-yl, —OC(═O)CH₂N(CH₃)₂,—OC(═O)CH₂-pyrrolidin-1-yl, or 1-methyl-piperidin-4-yloxy;

R¹ is C₁₋₆ alkyl;

R³ is H or halogen; and

R⁸ is selected from the group consisting of 5-methyl-isoxazol-4-yl,3-bromo-phenyl, 3-trifluoromethyl-phenyl, 3-methoxy-phenyl,4-chloro-phenyl, 3-chloro-phenyl, 2-chloro-phenyl, 4-fluoro-phenyl,2,4-difluoro-phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, phenyl,2-methoxy-phenyl, 4-trifluoromethoxy-phenyl, 3-trifluoromethoxy-phenyl,2-fluoro-4-methoxy-phenyl, 2-trifluoromethyl-phenyl,4-trifluoromethyl-phenyl, 4-bromo-phenyl, 3-cyano-phenyl, andcyclopropyl.

Some embodiments of the present invention pertain to certain compoundsof Formula (IIa) wherein:

wherein:

W is —CH₂CH₂—;

Q is —OH, —OCH₃, —OC(═O)CH₂-morpholin-4-yl, —OC(═O)CH₂N(CH₃)₂,—OC(═O)CH₂-pyrrolidin-1-yl, or 1-methyl-piperidin-4-yloxy;

R¹ is —CH₃;

R³ is H, or Cl; and

R⁸ is selected from the group consisting of 5-methyl-isoxazol-4-yl,3-bromo-phenyl, 3-trifluoromethyl-phenyl, 3-methoxy-phenyl,4-chloro-phenyl, 3-chloro-phenyl, 2-chloro-phenyl, 4-fluoro-phenyl,2,4-difluoro-phenyl, 3-fluoro-phenyl, 2-fluoro-phenyl, phenyl,2-methoxy-phenyl, 4-trifluoromethoxy-phenyl, 3-trifluoromethoxy-phenyl,2-fluoro-4-methoxy-phenyl, 2-trifluoromethyl-phenyl,4-trifluoromethyl-phenyl, 4-bromo-phenyl, 3-cyano-phenyl, andcyclopropyl.

In some embodiments, a compound of the present invention is other than acompound of Formula (III):

or a pharmaceutically acceptable salt, hydrate or solvate thereof;

wherein:

V² is O, S, S(═O), S(═O)₂ or NR³⁰;

W² is C₁₋₄ alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or8 substituents selected independently from the group consisting of C₁₋₃alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl, halogen and oxo; orW is absent;

X² is C(═O), C(═S) or absent;

Y² is O, NR³¹ or absent;

Z² is C₁₋₄ alkylene, or C₃₋₆ cycloalkylene, each optionally substitutedwith 1, 2, 3, 4, 5, 6, 7, or 8 substituents selected independently fromthe group consisting of C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃haloalkyl, halogen, hydroxyl, and oxo; or Z is absent;

R²¹ is selected from the group consisting of H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl and C₃₋₇ cycloalkyl;

R²² is selected from the group consisting of H, C₁₋₆ acyl, C₁₋₆ acyloxy,C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl,C₁₋₆ alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₂₋₈dialkylamino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₂₋₈ dialkylcarboxamide, C₂₋₈ dialkylsulfonamide, halogen,C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl, thiol, nitro andsulfonamide;

R²³ is selected from the group consisting of H, C₂₋₆ alkenyl, C₁₋₆alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylcarboxamide, halogen, heteroaryl and phenyl; and wherein each ofthe C₂₋₆ alkenyl, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₃₋₇cycloalkyl, heteroaryl and phenyl groups are optionally substituted with1, 2, 3, 4, or 5 substituents selected independently from the groupconsisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈alkyl, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,C₁₋₄ alkylthio, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl, nitro and sulfonamide;

R²⁴ is heterobicyclic, heterocyclic, or heteroaryl each optionallysubstituted with substituents selected independently from the groupconsisting of C₁₋₆ acyl, C₁₋₁₂ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₆alkoxycarbonylamino, C₁₋₆ alkyl, C₁₋₆ alkylamino, C₂₋₈ dialkylamino,C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl,C₃₋₇ cycloalkylcarbonyl, C₂₋₆ dialkylcarboxamide, formyl, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heteroaryl, hydroxyl, nitro,phenyl and sulfonamide; wherein the C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄alkoxy, C₁₋₆ alkyl, C₁₋₄ alkylcarboxamide, amino, carbo-C₁₋₆-alkoxy, andheteroaryl are each optionally substituted with substituents selectedindependently from the group consisting of C₁₋₆ alkyl, C₁₋₅ acyl, C₁₋₄alkoxy, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylsulfonyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₆ cycloalkyl, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, hydroxyl, andphenyl;

R²⁵, R²⁶, and R²⁷ are each selected independently from the groupconsisting of H, C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy,C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide,C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₆ alkylimino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylcarboxamide, C₂₋₈ dialkylsulfonamide, halogen, C₁₋₆ haloalkoxy,C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆haloalkylthio, heterocyclic, hydroxyl, thiol, nitro, phenoxy and phenyl;

R²⁸ is C₁₋₈ alkyl, C₂₋₆ alkenyl, aryl, C₃₋₇ cycloalkyl, or heteroaryleach optionally substituted with substituents selected independentlyfrom the group consisting of C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino,C₁₋₆ alkylimino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₂₋₈ dialkylcarboxamide, C₂₋₈ dialkylsulfonamide, halogen,C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, heterocyclic, hydroxyl, thiol,nitro, phenoxy and phenyl, or two adjacent substituents together withthe aryl or the heteroaryl form a C₅₋₇ cycloalkyl optionally comprising1 to 2 oxygen atoms and optionally substituted with F, Cl or Br; andwherein the C₂₋₆ alkenyl, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₁₋₆ alkylamino,C₁₋₆ alkylimino, C₂₋₈ dialkylamino, heterocyclic, and phenyl are eachoptionally substituted with 1, 2, 3, 4, or 5 substituents selectedindependently from the group consisting of C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl,C₁₋₆ alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylcarboxamide, halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆ haloalkylthio, hydroxyl,thiol and nitro; and

R²⁹, R³⁰, and R³¹ are each independently H or C₁₋₈ alkyl.

Some embodiments of the present invention include every combination ofone or more compounds selected from the following table:

Cmpd No. Chemical Structure Chemical Name 1

5-Methyl-isoxazole-3- carboxylic acid {3-(4- chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(3,3,3- trifluoro-propylamino)- ethoxy]-phenyl}-amide2

3-Bromo-N-[4-(2- methoxy-ethoxy)-3-(2- emthyl-2H-pyrazol-3-yl)-phenyl]-benzamide 3

N-{3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-[2-(2- hydroxy-ethylamino)-ethoxy]-phenyl}-3- trifluoromethyl-benzamide 4

N-[4-[2-(2- Methanesulfonyl- ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)- phenyl]-3-methoxy- benzamide 5

4-Chloro-N-[4-(2- methoxy-ethoxy)-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-benzamide 6

N-[3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-(2- ethylamino-2-methyl-propoxy)-phenyl]-3- trifluoromethyl-benzamide 7

3-Chloro-N-[4-(2- methoxy-ethoxy)-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-benzamide 8

5-Methyl-isoxazole-3- carboxylic acid {3-(4- chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(2- methanesulfonyl- ethylamino)-ethoxy]-phenyl}-amide 9

2-Chloro-N-[4-(2- methoxy-ethoxy)-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-benzamide 10

N-[4-[2-(2,2-Difluoro- propylamino)-ethoxy]-3- (2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy- benzamide 11

4-Fluoro-N-[4-(2-methoxy- ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]-benzamide 12

N-[3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-(2- ethylamino-ethoxy)-phenyl]-3-trifluoromethyl- benzamide 13

2,4-Difluoro-N-[4-[2-(2- hydroxy-ethylamino)- ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]- benzamide 14

3-Fluoro-N-[4-(2-methoxy- ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]-benzamide 15

N-{3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-[2-(2- methoxy-ethylamino)-ethoxy]-phenyl}-3- trifluoromethyl-benzamide 16

N-[4-[2-(2-Cyano- ethylamino)-ethoxy]-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro- benzamide 17

2-Fluoro-N-[4-(2-methoxy- ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]-benzamide 18

N-{3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-[2- (1,1-dimethyl-propylamino)-ethoxy]- phenyl}-3-trifluoromethyl- benzamide 19

2,4-Difluoro-N-{3-(2- methyl-2H-pyrazol-3-yl)- 4-[2-(tetrahydro-pyran-4-ylamino)-ethoxy]-phenyl}- benzamide 20

N-[4-(2-Methoxy-ethoxy)- 3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-benzamide21

N-[4-(2- Acetimidoylamino- ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3- methoxy-benzamide 22

N-{3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-[2- (piperidin-4-ylamino)-ethoxy]-phenyl}-3-fluoro- benzamide 23

4-{2-[2-(4-Chloro-2- methyl-2H-pyrazol-3-yl)- 4-(3-trifluoromethyl-benzoylamino)-phenoxy]- ethylamino}-piperidine-1- carboxylic acidtert-butyl ester 24

4-{2-[2-(4-Chloro-2- methyl-2H-pyrazol-3-yl)- 4-(3-methoxy-benzoylamino)-phenoxy]- ethylamino}-piperidine-1- carboxylic acidtert-butyl ester 25

4-Methoxy-N-[4-(2- methoxy-ethoxy)-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-benzamide 26

N-[4-(2-Butylamino- ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]-3-methoxy-benzamide 27

2,4-Difluoro-N-[4-[2-(1- methyl-piperidin-4- ylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)- phenyl]-benzamide 28

3-Fluoro-N-[4-[2-(2- methanesulfonyl- ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)- phenyl]-benzamide 29

N-[4-[2- (Carbamoylmethyl-amino)- ethoxy]-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)- phenyl]-3-trifluoromethyl- benzamide 30

3-Methoxy-N-[4-(2- methoxy-ethoxy)-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-benzamide 31

N-[3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-(2- isobutylamino-ethoxy)-phenyl]-3-trifluoromethyl- benzamide 32

N-{3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-[2- (piperidin-4-ylamino)-ethoxy]-phenyl}-3- methoxy-benzamide 33

N-[4-[2-(Cyanomethyl- amino)-ethoxy]-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy- benzamide 34

N-{3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-[2-(1- methyl-piperidin-4-ylamino)-ethoxy]-phenyl}- 3-fluoro-benzamide 35

2-Methoxy-N-[4-(2- methxoy-ethoxy)-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-benzamide 36

N-[4-(2-Benzylamino- ethoxy)-3-(4-chloro-2- methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl- benzamide 37

N-[4-[2-(2-Fluoro- ethylamino)-ethoxy]-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy- benzamide 38

3-Methoxy-N-[4-[2-(2- methoxy-ethylamino)- ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]- benzamide 39

4-{2-[2-(4-Chloro-2- methyl-2H-pyrazol-3-yl)- 4-(3-trifluoromethyl-benzoylamino)-phenoxy]- ethylamino}-piperidine-1- carboxylic acid ethylester 40

N-[4-(2-Methoxy-ethoxy)- 3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-4-trifluoromethoxy- benzamide 41

N-{3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-[2-(1- methyl-piperidin-4-ylamino)-ethoxy]-phenyl}- 3-methoxy-benzamide 42

3-Fluoro-N-{3-(2-methyl- 2H-pyrazol-3-yl)-4-[2-(1H-[1,2,4]triazol-3-ylamino)- ethoxy]-phenyl}- benzamide 43

N-[4-[2-(2-Hydroxy- ethylamino)-ethoxy]-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy- benzamide 44

N-[4-(2-Guanidino- ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]-3-methoxy-benzamide 45

N-{3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-[2-(1- methyl-piperidin-4-ylamino)-ethoxy]-phenyl}- 3-trifluoromethyl- benzamide 46

N-[4-(2-Methoxy-ethoxy)- 3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-3-trifluoromethoxy- benzamide 47

N-[3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-(2-cyclopropylamino-ethoxy)- phenyl]-3-trifluoromethyl- benzamide 48

3-Fluoro-N-{3-(2-methyl- 2H-pyrazol-3-yl)-4-[2-(4-methyl-thiazol-2-ylamino)- ethoxy]-phenyl}- benzamide 49

N-{3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-[2- ((R)-6-oxo-piperidin-3-ylamino)-ethoxy]-phenyl}- 3-methoxy-benzamide 50

N-{3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-[(2-methoxy-ethylcarbamoyl)- methoxy]-phenyl}-3- trifluoromethyl-benzamide51

N-{3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-[2- (tetrahydro-pyran-4-ylamino)-ethoxy]-phenyl}- 3-fluoro-benzamide 52

N-[4-(2-Methoxy-ethoxy)- 3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-3-trifluoromethyl-benzamide 53

N-{3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-[2- (tetrahydro-pyran-4-ylamino)-ethoxy]-phenyl}- 3-methoxy-benzamide 54

3-Fluoro-N-{3-(2-methyl- 2H-pyrazol-3-yl)-4-[2-(1H- tetrazol-5-ylamino)-ethoxy]-phenyl}- benzamide 55

N-[4-[2-(2-Ethoxy- ethylamino)-ethoxy]-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy- benzamide 56

N-{3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-[2- (3,3,3-trifluoro-propylamino)-ethoxy]- phenyl}-2-fluoro-4- methoxy-benzamide 57

N-[4-(2-Methoxy-ethoxy)- 3-(2-methyl-2H-pyrazol-3- yl)-phenyl]-2-trifluoromethyl-benzamide 58

N-{3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-[2-(2- fluoro-ethylamino)-ethoxy]-phenyl}-3- trifluoromethyl-benzamide 59

N-[4-[2-(2-Hydroxy- ethylamino)-ethoxy]-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl- benzamide 60

N-{3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-[2- (piperidin-4-ylamino)-ethoxy]-phenyl}-3- trifluoromethyl-benzamide 61

N-{3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-[2- (tetrahydro-pyran-4-ylamino)-ethoxy]-phenyl}- 3-trifluoromethyl- benzamide 62

4-Bromo-N-[4-(2- methoxy-ethoxy)-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-benzamide 63

N-[4-[2-(2-Isopropoxy- ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)- phenyl]-3-methoxy- benzamide 64

4-{2-[2-(4-Chloro-2- methyl-2H-pyrazol-3-yl)- 4-(3-fluoro-benzoylamino)-phenoxy]- ethylamino}-piperidin-1- carboxylic acidtert-butyl ester 65

Cyclopropanecarboxylic acid {3-(4-chloro-2- methyl-2H-pyrazol-3-yl)-4-[2-(2-hydroxy- ethylamino)-ethoxy]- phenyl}-amide 66

N-[4-(2-tert-Butylamino- ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3- methoxy-benzamide 67

N-[3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-(2- methyl-2-propylamino-propoxy)-phenyl]-3- trifluoromethyl-benzamide 68

N-[3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-(2- hydroxy-ethoxy)-phenyl]-3-methoxy-benzamide 69

3-Fluoro-N-[4-[2-(2- hydroxy-ethylamino)- ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]- benzamide 70

N-[4-[2-(2-Cyano- ethylamino)-ethoxy]-3-(2- methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy- benzamide 71

N-{3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-[2-(1-methyl-piperidin-4-yloxy)- ethoxy]-phenyl}-3- methoxy-benzamide 72

3-Methoxy-N-{3-(2- methyl-2H-pyrazol-3-yl)- 4-[2-(3,3,3-trifluoro-propylamino)-ethoxy]- phenyl}-benzamide 73

N-{3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-[2-(1-methyl-piperidin-4-yloxy)- ethoxy]-phenyl}-3-fluoro- benzamide 74

N-[4-(2-Isopropylamino- ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]-3-methoxy-benzamide 75

N-[4-(2-Butylamino-2- methyl-propoxy)-3-(4- chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3- trifluoromethyl-benzamide 76

N-[3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-(2- hydroxy-ethoxy)-phenyl]-3-fluoro-benzamide 77

3-Fluoro-N-{2-(2-methyl- 2H-pyrazol-3-yl)-4-[2- (3,3,3-trifluoro-propylamino)-ethoxy]- phenyl}-benzamide 78

N-{3-(4-Chloro-2-methyl- 2H-pyrazol-3-yl)-4-[2-(1-methyl-piperidin-4-yloxy)- ethoxy]-phenyl}-3- trifluoromethyl-benzamide79

3-Methoxy-N-[3-(2- methyl-2H-pyrazol-3-yl)- 4-(2-propylamino-ethoxy)-phenyl]-benzamide 80

N-[4-[2-(3-Cyano- propylamino)-ethoxy]-3- (2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy- benzamide 81

3-Cyano-N-[4-(2-methoxy- ethoxy)-3-(2-methyl-2H- pyrazol-3-yl)-phenyl]-benzamide 82

Morpholin-4-yl-acetic acid 2-[2-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(3- methoxy-benzoylamino)- phenoxy]-ethyl ester 83

Dimethylamino-acetic acid 2-[2-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(3- methoxy-benzoylamino)- phenoxy]-ethyl ester 84

Pyrrolidin-1-yl-acetic acid 2-[2-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-(3- methoxy-benzoylamino)- phenxoy]-ethyl ester

Additionally, individual compounds and chemical genera of the presentinvention, such as Formula (Ia) and related Formulae therefrom,encompass all pharmaceutically acceptable salts, solvates, andparticularly hydrates, thereof.

It is understood that the present invention embraces each diastereomer,each enantiomer and mixtures thereof of each compound and genericFormulae disclosed herein just as if they were each individuallydisclosed with the specific stereochemical designation for each chiralatom, for example carbon. Separation of the individual isomers (such as,chiral HPLC, recrystallization of diastereomeric mixture, and the like)or selective synthesis (such as, enantiomeric selective synthesis, andthe like) of the individual isomers is accomplished by application ofvarious methods which are well known to practitioners in the art.

The compounds of the Formula (Ia) of the present invention can beprepared according to the general synthetic schemes in FIGS. 1 through 8as well as relevant published literature procedures that are used by oneskilled in the art. Exemplary reagents and procedures for thesereactions appear hereinafter in the working Examples. Protection anddeprotection may be carried out by procedures generally known in the art(see, for example, Greene, T. W. and Wuts, P. G. M., Protecting Groupsin Organic Synthesis, 3^(rd) Edition, 1999 [Wiley]; incorporated hereinby reference in its entirety).

Indications and Methods of Treatment

In addition to the foregoing beneficial uses for the modulators of5-HT_(2A) receptor activity disclosed herein, the compounds disclosedherein are believed to be useful in the treatment of several additionaldiseases and disorders, and in the amelioration of symptoms thereof.Without limitation, these include the following:

1. Antiplatelet Therapies (Conditions Related to Platelet Aggregation):

Antiplatelet agents (antiplatelets) are prescribed for a variety ofconditions. For example, in coronary artery disease they are used tohelp prevent myocardial infarction or stroke in patients who are at riskof developing obstructive blood clots (e.g., coronary thrombosis).

In a myocardial infarction (heart attack), the heart muscle does notreceive enough oxygen-rich blood as a result of a blockage in thecoronary blood vessels. If taken while an attack is in progress orimmediately afterward (preferably within 30 minutes), antiplatelets canreduce the damage to the heart.

A transient ischemic attack (“TIA” or “mini-stroke”) is a briefinterruption of oxygen flow to the brain due to decreased blood flowthrough arteries, usually due to an obstructing blood clot. Antiplateletdrugs have been found to be effective in preventing TIAs.

Angina is a temporary and often recurring chest pain, pressure ordiscomfort caused by inadequate oxygen-rich blood flow (ischemia) tosome parts of the heart. In patients with angina, antiplatelet therapycan reduce the effects of angina and the risk of myocardial infarction.

Stroke is an event in which the brain does not receive enoughoxygen-rich blood, usually due to blockage of a cerebral blood vessel bya blood clot. In high-risk patients, taking antiplatelets regularly hasbeen found to prevent the formation of blood clots that cause first orsecond strokes.

Angioplasty is a catheter based technique used to open arteriesobstructed by a blood clot. Whether or not stenting is performedimmediately after this procedure to keep the artery open, antiplateletscan reduce the risk of forming additional blood clots following theprocedure(s).

Coronary bypass surgery is a surgical procedure in which an artery orvein is taken from elsewhere in the body and grafted to a blockedcoronary artery, rerouting blood around the blockage and through thenewly attached vessel. After the procedure, antiplatelets can reduce therisk of secondary blood clots.

Atrial fibrillation is the most common type of sustained irregular heartrhythm (arrythmia). Atrial fibrillation affects about two millionAmericans every year. In atrial fibrillation, the atria (the heart'supper chambers) rapidly fire electrical signals that cause them toquiver rather than contract normally. The result is an abnormally fastand highly irregular heartbeat. When given after an episode of atrialfibrillation, antiplatelets can reduce the risk of blood clots formingin the heart and traveling to the brain (embolism).

5-HT_(2A) receptors are expressed on smooth muscle of blood vessels and5-HT secreted by activated platelets causes vasoconstriction as well asactivation of additional platelets during clotting. There is evidencethat a 5-HT_(2A) inverse agonist will inhibit platelet aggregation andthus be a potential treatment as an antiplatelet therapy (see Satimura,K, et al., Clin Cardiol 2002 Jan. 25 (1):28-32; and Wilson, H. C et al.,Thromb Haemost 1991 Sep. 2; 66(3):355-60).

5-HT_(2A) inverse agonists can be used to treat, for example,claudication or peripheral artery disease as well as cardiovascularcomplications (see Br. Med. J. 298: 424-430, 1989), Arterial thrombosis(see, Pawlak, D. et al. Thrombosis Research 90: 259-270, 1998),atherosclerosis (see, Hayashi, T. et al. Atherosclerosis 168: 23-31,2003), vasoconstriction, caused by serotonin (see, Fujiwara, T. andChiba, S. Journal of Cardiovascular Pharmacology 26: 503-510, 1995),restenosis of arteries following angioplasty or stent placement (see,Fujita, M. et al. Am Heart J. 145:e16 2003). It can also be used aloneor in combination with thrombolytic therapy, for example, tPA (see,Yamashita, T. et al. Haemostasis 30:321-332, 2000), to providecardioprotection following MI or postischemic myocardial dysfunction(see, Muto, T. et al. Mol. Cell. Biochem. 272: 119-132, 2005) orprotection from ischemic injury during percutaneous coronaryintervention (see, Horibe, E. Circulation Research 68: 68-72, 2004), andthe like, including complications resulting therefrom.

5-HT_(2A) inverse antagonists can increase circulating adiponectin inpatients, suggesting that they would also be useful in protectingpatients against indications that are linked to adiponectin, forexample, myocardial ischemia reperfusion injury and artherosclerosis(see Nomura, Shosaku, et al. Blood Coagulation and Fibrinolysis 2005,16, 423-428).

The 5-HT_(2A) inverse agonists disclosed herein provide beneficialimprovement in microcirculation to patients in need of antiplatelettherapy by antagonizing the vasoconstrictive products of the aggregatingplatelets in, for example and not limited to the indications describedabove. Accordingly, in some embodiments, the present invention providesmethods for reducing platelet aggregation in a patient in need thereofcomprising administering to the patient a composition comprising a5-HT_(2A) inverse agonist disclosed herein. In further embodiments, thepresent invention provides methods for treating coronary artery disease,myocardial infarction, transient ischemic attack, angina, stroke, atrialfibrillation, or a symptom of any of the foregoing in a patient in needof the treatment, comprising administering to the patient a compositioncomprising a 5-HT_(2A) inverse agonist disclosed herein.

In further embodiments, the present invention provides methods forreducing risk of blood clot formation in an angioplasty or coronarybypass surgery patient, or a patient suffering from atrial fibrillation,comprising administering to the patient a composition comprising a5-HT_(2A) inverse agonist disclosed herein at a time where such riskexists.

One aspect of the present invention provides a therapeutic agent fortreating indications associated with the pathophysiology of plateletaggregation used in combination with compounds of the present inventionas disclosed herein. Accordingly, compounds of the present invention canbe used alone or in combination with other therapeutic agent(s), suchas, thromboxane A2 blocker (aspirin and the like), and ADP-mediatedplatelet aggregation inhibitor (ticlopidine, clopidogrel, and the like)either administered together or separately.

2. Asthma

5-HT (5-hydroxytryptamine) has been linked to the pathophysiology ofacute asthma (see Cazzola, M. and Matera, M. G., TIPS, 2000, 21, 13; andDe Bie, J. J. et al., British J. Pharm., 1998, 124, 857-864). Thecompounds of the present invention disclosed herein are useful in thetreatment of asthma, and the treatment of the symptoms thereof.Accordingly, in some embodiments, the present invention provides methodsfor treating asthma in a patient in need of the treatment, comprisingadministering to the patient a composition comprising a 5-HT_(2A)inverse agonist disclosed herein. In further embodiments, methods areprovided for treating a symptom of asthma in a patient in need of thetreatment, comprising administering to the patient a compositioncomprising a 5-HT_(2A) inverse agonist disclosed herein.

3. Agitation

Agitation is a well-recognized behavioral syndrome with a range ofsymptoms, including hostility, extreme excitement, poor impulse control,tension and uncooperativeness (See Cohen-Mansfield J, and Billig, N.,(1986), Agitated Behaviors in the Elderly. I. A Conceptual Review. J AmGeriatr Soc 34(10): 711-721).

Agitation is a common occurrence in the elderly and often associatedwith dementia such as those caused by Alzheimer's disease, Lewy body,Parkinson's, and Huntington's, which are degenerative diseases of thenervous system and by diseases that affect blood vessels, such asstroke, or multi-infarct dementia, which is caused by multiple strokesin the brain can also induce dementia. Alzheimer's disease accounts forapproximately 50 to 70% of all dementias (See Koss E, et al., (1997),Assessing patterns of agitation in Alzheimer's disease patients with theCohen-Mansfield Agitation Inventory. The Alzheimer's Disease CooperativeStudy. Alzheimer Dis Assoc Disord 11(suppl 2):545-S50).

An estimated five percent of people aged 65 and older and up to 20percent of those aged 80 and older are affected by dementia; of thesesufferers, nearly half exhibit behavioral disturbances, such asagitation, wandering and violent outbursts.

Agitated behaviors can also be manifested in cognitively intact elderlypeople and by those with psychiatric disorders other than dementia.

Agitation is often treated with antipsychotic medications such ashaloperidol in nursing home and other assisted care settings. There isemerging evidence that agents acting at the 5-HT_(2A) receptors in thebrain have the effects of reducing agitation in patients, includingAlzheimer's dementia (See Katz, I. R., et al., J Clin Psychiatry 1999February, 60(2):107-115; and Street, J. S., et al., Arch Gen Psychiatry2000 October, 57(10):968-976).

The compounds of the invention disclosed herein are useful for treatingagitation and symptoms thereof. Thus, in some embodiments, the presentinvention provides methods for treating agitation in a patient in needof such treatment comprising administering to the patient a compositioncomprising a 5-HT_(2A) inverse agonist disclosed herein. In someembodiments, the agitation is due to a psychiatric disorder other thandementia. In some embodiments, the present invention provides methodsfor treatment of agitation or a symptom thereof in a patient sufferingfrom dementia comprising administering to the patient a compositioncomprising a 5-HT_(2A) inverse agonist disclosed herein. In someembodiments of such methods, the dementia is due to a degenerativedisease of the nervous system, for example and without limitation,Alzheimers disease, Lewy body, Parkinson's disease, and Huntington'sdisease, or dementia due to diseases that affect blood vessels,including, without limitation, stroke and multi-infarct dementia. Insome embodiments, methods are provided for treating agitation or asymptom thereof in a patient in need of such treatment, where thepatient is a cognitively intact elderly patient, comprisingadministering to the patient a composition comprising a 5-HT_(2A)inverse agonist disclosed herein.

4. Add-on Therapy to Haloperidol in the Treatment of Schizophrenia andOther Disorders:

Schizophrenia is a psychopathic disorder of unknown origin, whichusually appears for the first time in early adulthood and is marked by anumber of characteristics, psychotic symptoms, progression, phasicdevelopment and deterioration in social behavior and professionalcapability in the region below the highest level ever attained.Characteristic psychotic symptoms are disorders of thought content(multiple, fragmentary, incoherent, implausible or simply delusionalcontents or ideas of persecution) and of mentality (loss of association,flight of imagination, incoherence up to incomprehensibility), as wellas disorders of perceptibility (hallucinations), of emotions(superficial or inadequate emotions), of self-perception, of intentionsand impulses, of interhuman relationships, and finally psychomotoricdisorders (such as catatonia). Other symptoms are also associated withthis disorder. (See, American Statistical and Diagnostic Handbook).

Haloperidol (Haldol) is a potent dopamine D₂ receptor antagonist. It iswidely prescribed for acute schizophrenic symptoms, and is veryeffective for the positive symptoms of schizophrenia. However, Haldol isnot effective for the negative symptoms of schizophrenia and mayactually induce negative symptoms as well as cognitive dysfunction. Inaccordance with some methods of the invention, adding a 5-HT_(2A)inverse agonist concomitantly with Haldol will provide benefitsincluding the ability to use a lower dose of Haldol without losing itseffects on positive symptoms, while reducing or eliminating itsinductive effects on negative symptoms, and prolonging relapse to thepatient's next schizophrenic event.

Haloperidol is used for treatment of a variety of behavioral disorders,drug induced psychosis, excitative psychosis, Gilles de la Tourette'ssyndrome, manic disorders, psychosis (organic and NOS), psychoticdisorder, psychosis, schizophrenia (acute, chronic and NOS). Furtheruses include in the treatment of infantile autism, huntington's chorea,and nausea and vomiting from chemotherapy and chemotherapeuticantibodies. Administration of 5-HT_(2A) inverse agonists disclosedherein with haloperidol also will provide benefits in these indications.

In some embodiments, the present invention provides methods for treatinga behavioral disorder, drug induced psychosis, excitative psychosis,Gilles de la Tourette's syndrome, manic disorders, psychosis (organicand NOS), psychotic disorder, psychosis, schizophrenia (acute, chronicand NOS) comprising administering to the patient a dopamine D₂ receptorantagonist and a 5-HT_(2A) inverse agonist disclosed herein.

In some embodiments, the present invention provides methods for treatinga behavioral disorder, drug induced psychosis, excitative psychosis,Gilles de la Tourette's syndrome, manic disorders, psychosis (organicand NOS), psychotic disorder, psychosis, schizophrenia (acute, chronicand NOS) comprising administering to the patient haloperidol and a5-HT_(2A) inverse agonist disclosed herein.

In some embodiments, the present invention provides methods for treatinginfantile autism, huntington's chorea, or nausea and vomiting fromchemotherapy or chemotherapeutic antibodies comprising administering tothe patient a dopamine D₂ receptor antagonist and a 5-HT_(2A) inverseagonist disclosed herein.

In some embodiments, the present invention provides methods for treatinginfantile autism, huntington's chorea, or nausea and vomiting fromchemotherapy or chemotherapeutic antibodies comprising administering tothe patient haloperidol and a 5-HT_(2A) inverse agonist disclosedherein.

In further embodiments, the present invention provides methods fortreating schizophrenia in a patient in need of the treatment comprisingadministering to the patient a dopamine D₂ receptor antagonist and a5-HT_(2A) inverse agonist disclosed herein. Preferably, the dopamine D₂receptor antagonist is haloperidol.

The administration of the dopamine D₂ receptor antagonist can beconcomitant with administration of the 5-HT_(2A) inverse agonist, orthey can be administered at different times. Those of skill in the artwill easily be able to determine appropriate dosing regimes for the mostefficacious reduction or elimination of deleterious haloperidol effects.In some embodiments, haloperidol and the 5-HT_(2A) inverse agonist areadministered in a single dosage form, and in other embodiments, they areadministered in separate dosage forms.

The present invention further provides methods of alleviating negativesymptoms of schizophrenia induced by the administration of haloperidolto a patient suffering from schizophrenia, comprising administering tothe patient a 5-HT_(2A) inverse agonist as disclosed herein.

5. Sleep Disorders

It is reported in the National Sleep Foundation's 2002 Sleep In AmericaPoll, more than one-half of the adults surveyed (58%) report havingexperienced one or more symptoms of insomnia at least a few nights aweek in the past year. Additionally, about three in ten (35%) say theyhave experienced insomnia-like symptoms every night or almost everynight.

The normal sleep cycle and sleep architecture can be disrupted by avariety of organic causes as well as environmental influences. Accordingto the International Classification of Sleep Disorders, there are over80 recognized sleep disorders. Of these, compounds of the presentinvention are effective, for example, in any one or more of thefollowing sleep disorders (ICSD—International Classification of SleepDisorders: Diagnostic and Coding Manual. Diagnostic ClassificationSteering Committee, American Sleep Disorders Association, 1990):

A. Dyssomnias

a. Intrinsic Sleep Disorders:

Psychophysiological insomnia, Sleep state misperception, Idiopathicinsomnia, Obstructive sleep apnea syndrome, Central sleep apneasyndrome, Central alveolar hypoventilation syndrome, Periodic limbmovement disorder, Restless leg syndrome and Intrinsic sleep disorderNOS.

b. Extrinsic Sleep Disorders:

Inadequate sleep hygiene, Environmental sleep disorder, Altitudeinsomnia, Adjustment sleep disorder, Insufficient sleep syndrome,Limit-setting sleep disorder, SleepOnset association disorder, Nocturnaleating (drinking) syndrome, Hypnotic dependent sleep disorder,Stimulant-dependent sleep disorder, Alcohol-dependent sleep disorder,Toxin-induced sleep disorder and Extrinsic sleep disorder NOS.

c. Circadian Rhythm Sleep Disorders:

Time zone change (jet lag) syndrome, Shift work sleep disorder,Irregular sleep-wake pattern, Delayed sleep phase syndrome, Advancedsleep phase syndrome, Non-24-hour sleep-wake disorder and Circadianrhythm sleep disorder NOS.

B. Parasomnias

a. Arousal Disorders:

Confusional arousals, Sleepwalking and Sleep terrors.

b. Sleep-Wake Transition Disorders:

Rhythmic movement disorder, Sleep starts, Sleep talking and Nocturnalleg cramps.

C. Sleep Disorders Associated with Medical/Psychiatric Disorders

a. Associated with Mental Disorders:

Psychoses, Mood disorders, Anxiety disorders, Panic disorders andAlcoholism.

b. Associated with Neurological Disorders:

Cerebral degenerative disorders, Dementia, Parkinsonism, Fatal familialinsomnia, Sleep-related epilepsy, Electrical status epilepticus of sleepand Sleep-related headaches.

c. Associated with Other Medical Disorders:

Sleeping sickness, Nocturnal cardiac ischemia, Chronic obstructivepulmonary disease, Sleep-related asthma, Sleep-related gastroesophagealreflux, Peptic ulcer disease, Fibrositis syndrome, Osteoarthritis,Rheumatoid arthritis, Fibromyalgia and Post-surgical.

The effects of sleep deprivation are more than excessive daytimesleepiness. Chronic insomniacs report elevated levels of stress,anxiety, depression and medical illnesses (National Institutes ofHealth, National Heart, Lung, and Blood Institute, Insomnia Facts Sheet,October 1995). Preliminary evidence suggests that having a sleepdisorder that causes significant loss of sleep may contribute toincreased susceptibility to infections due to immunosuppression,cardiovascular complications such as hypertension, cardiac arrhythmias,stroke, and myocardial infarction, compromised glucose tolerance,increased obesity and metabolic syndrome. Compounds of the presentinvention are useful to prevent or alleviate these complications byimproving sleep quality.

The most common class of medications for the majority of sleep disordersare the benzodiazepines, but the adverse effect profile ofbenzodiazepines include daytime sedation, diminished motor coordination,and cognitive impairments. Furthermore, the National Institutes ofHealth Consensus conference on Sleeping Pills and Insomnia in 1984 havedeveloped guidelines discouraging the use of such sedative-hypnoticsbeyond 4-6 weeks because of concerns raised over drug misuse,dependency, withdrawal and rebound insomnia. Therefore, it is desirableto have a pharmacological agent for the treatment of insomnia, which ismore effective and/or has fewer side effects than those currently used.In addition, benzodiazepines are used to induce sleep, but have littleto no effect on the maintenance of sleep, sleep consolidation or slowwave sleep. Therefore, sleep maintenance disorders are not currentlywell treated.

Clinical studies with agents of a similar mechanism of action as arecompounds of the present invention have demonstrated significantimprovements on objective and subjective sleep parameters in normal,healthy volunteers as well as patients with sleep disorders and mooddisorders [Sharpley A L, et al. Slow Wave Sleep in Humans: Role of5-HT_(2A) and 5HT_(2C) Receptors. Neuropharmacology, 1994, Vol.33(3/4):467-71; Winokur A, et al. Acute Effects of Mirtazapine on SleepContinuity and Sleep Architecture in Depressed Patients: A Pilot Study.Soc of Biol Psych, 2000, Vol. 48:75-78; and Landolt H P, et al.Serotonin-2 Receptors and Human Sleep: Effect of Selective Antagonist onEEG Power Spectra. Neuropsychopharmacology, 1999, Vol. 21(3):455-66].

Some sleep disorders are sometimes found in conjunction with otherconditions and accordingly those conditions are treatable by compoundsof Formula (Ia). For example, but not limited to, patients sufferingfrom mood disorders typically suffer from a sleep disorder that can betreatable by compounds of Formula (Ia). Having one pharmacological agentwhich treats two or more existing or potential conditions, as does thepresent invention, is more cost effective, leads to better complianceand has fewer side effects than taking two or more agents.

It is an object of the present invention to provide a therapeutic agentfor the use in treating Sleep Disorders. It is another object of thepresent invention to provide one pharmaceutical agent, which may beuseful in treating two or more conditions wherein one of the conditionsis a sleep disorder. Compounds of the present invention described hereinmay be used alone or in combination with a mild sleep inducer, such as,a sedating antihistamine (diphenhydramine, chloropheniramine,bromopheniramine and the like), GABA-A receptor modulators (Ambien,Sonata, Indiplon, Gaboxadol, and the like), melatonin agonists (ML1receptor agonist, such as Ramelteon and the like), sedatingantidepressants (such as a tricyclic antidepressant, doxepine and thelike), and benzodiazepines (diazepam and the like) and eitheradministered together or separately.

Sleep Architecture:

Sleep comprises two physiological states: Non rapid eye movement (NREM)and rapid eye movement (REM) sleep. NREM sleep consists of four stages,each of which is characterized by progressively slower brain wavepatterns, with the slower patterns indicating deeper sleep. So calleddelta sleep, stages 3 and 4 of NREM sleep, is the deepest and mostrefreshing type of sleep. Many patients with sleep disorders are unableto adequately achieve the restorative sleep of stages 3 and 4. Inclinical terms, patients' sleep patterns are described as fragmented,meaning the patient spends a lot of time alternating between stages 1and 2 (semi-wakefulness) and being awake and very little time in deepsleep. As used herein, the term “fragmented sleep architecture” means anindividual, such as a sleep disorder patient, spends the majority oftheir sleep time in NREM sleep stages 1 and 2, lighter periods of sleepfrom which the individual can be easily aroused to a Waking state bylimited external stimuli. As a result, the individual cycles throughfrequent bouts of light sleep interrupted by frequent awakeningsthroughout the sleep period. Many sleep disorders are characterized by afragmented sleep architecture. For example, many elderly patients withsleep complaints have difficulty achieving long bouts of deep refreshingsleep (NREM stages 3 and 4) and instead spend the majority of theirsleep time in NREM sleep stages 1 and 2.

In contrast to fragmented sleep architecture, as used herein the term“sleep consolidation” means a state in which the number of NREM sleepbouts, particularly Stages 3 and 4, and the length of those sleep boutsare increased, while the number and length of waking bouts aredecreased. In essence, the architecture of the sleep disorder patient isconsolidated to a sleeping state with increased periods of sleep andfewer awakenings during the night and more time is spent in slow wavesleep (Stages 3 and 4) with fewer oscillation Stage 1 and 2 sleep.Compounds of the present invention can be effective in consolidatingsleep patterns so that the patient with previously fragmented sleep cannow achieve restorative, delta-wave sleep for longer, more consistentperiods of time.

As sleep moves from stage 1 into later stages, heart rate and bloodpressure drop, metabolic rate and glucose consumption fall, and musclesrelax. In normal sleep architecture, NREM sleep makes up about 75% oftotal sleep time; stage 1 accounting for 5-10% of total sleep time,stage 2 for about 45-50%, stage 3 approximately 12%, and stage 4 13-15%.About 90 minutes after sleep onset, NREM sleep gives way to the firstREM sleep episode of the night. REM makes up approximately 25% of totalsleep time. In contrast to NREM sleep, REM sleep is characterized byhigh pulse, respiration, and blood pressure, as well as otherphysiological patterns similar to those seen in the active waking stage.Hence, REM sleep is also known as “paradoxical sleep.” Sleep onsetoccurs during NREM sleep and takes 10-20 minutes in healthy youngadults. The four stages of NREM sleep together with a REM phase form onecomplete sleep cycle that is repeated throughout the duration of sleep,usually four or five times. The cyclical nature of sleep is regular andreliable; a REM period occurs about every 90 minutes during the night.However, the first REM period tends to be the shortest, often lastingless than 10 minutes, whereas the later REM periods may last up to 40minutes. With aging, the time between retiring and sleep onset increasesand the total amount of night-time sleep decreases because of changes insleep architecture that impair sleep maintenance as well as sleepquality. Both NREM (particularly stages 3 and 4) and REM sleep arereduced. However, stage 1 NREM sleep, which is the lightest sleep,increases with age.

As used herein, the term “delta power” means a measure of the durationof EEG activity in the 0.5 to 3.5 Hz range during NREM sleep and isthought to be a measure of deeper, more refreshing sleep. Delta power ishypothesized to be a measure of a theoretical process called Process Sand is thought to be inversely related to the amount of sleep anindividual experiences during a given sleep period. Sleep is controlledby homeostatic mechanisms; therefore, the less one sleeps the greaterthe drive to sleep. It is believed that Process S builds throughout thewake period and is discharged most efficiently during delta power sleep.Delta power is a measure of the magnitude of Process S prior to thesleep period. The longer one stays awake, the greater Process S or driveto sleep and thus the greater the delta power during NREM sleep.However, individuals with sleep disorders have difficulty achieving andmaintaining delta wave sleep, and thus have a large build-up of ProcessS with limited ability to discharge this buildup during sleep. 5-HT_(2A)agonists tested preclinically and clinically mimic the effect of sleepdeprivation on delta power, suggesting that subjects with sleepdisorders treated with a 5-HT_(2A) inverse agonist or antagonist will beable to achieve deeper more refreshing sleep. These same effects havenot been observed with currently marketed pharmacotherapies. Inaddition, currently marketed pharmacotherapies for sleep have sideeffects such as hangover effects or addiction that are associated withthe GABA receptor. 5-HT_(2A) inverse agonists do not target the GABAreceptor and so these side effects are not a concern.

Subjective and Objective Determinations of Sleep Disorders:

There are a number of ways to determine whether the onset, duration orquality of sleep (e.g. non-restorative or restorative sleep) is impairedor improved. One method is a subjective determination of the patient,e.g., do they feel drowsy or rested upon waking. Other methods involvethe observation of the patient by another during sleep, e.g., how longit takes the patient to fall asleep, how many times does the patientwake up during the night, how restless is the patient during sleep, etc.Another method is to objectively measure the stages of sleep usingpolysomnography.

Polysomnography is the monitoring of multiple electrophysiologicalparameters during sleep and generally includes measurement of EEGactivity, electroculographic activity and electromyographic activity, aswell as other measurements. These results, along with observations, canmeasure not only sleep latency (the amount of time required to fallasleep), but also sleep continuity (overall balance of sleep andwakefulness) and sleep consolidation (percent of sleeping time spent indelta-wave or restorative sleep) which may be an indication of thequality of sleep.

There are five distinct sleep stages, which can be measured bypolysomnography: rapid eye movement (REM) sleep and four stages ofnon-rapid eye movement (NREM) sleep (stages 1, 2, 3 and 4). Stage 1 NREMsleep is a transition from wakefulness to sleep and occupies about 5% oftime spent asleep in healthy adults. Stage 2 NREM sleep, which ischaracterized by specific EEG waveforms (sleep spindles and Kcomplexes), occupies about 50% of time spent asleep. Stages 3 and 4 NREMsleep (also known collectively as slow-wave sleep and delta-wave sleep)are the deepest levels of sleep and occupy about 10-20% of sleep time.REM sleep, during which the majority of vivid dreams occur, occupiesabout 20-25% of total sleep.

These sleep stages have a characteristic temporal organization acrossthe night. NREM stages 3 and 4 tend to occur in the first one-third toone-half of the night and increase in duration in response to sleepdeprivation. REM sleep occurs cyclically through the night. Alternatingwith NREM sleep about every 80-100 minutes. REM sleep periods increasein duration toward the morning. Human sleep also variescharacteristically across the life span. After relative stability withlarge amounts of slow-wave sleep in childhood and early adolescence,sleep continuity and depth deteriorate across the adult age range. Thisdeterioration is reflected by increased wakefulness and stage 1 sleepand decreased stages 3 and 4 sleep.

In addition, the compounds of the invention can be useful for thetreatment of the sleep disorders characterized by excessive daytimesleepiness such as narcolepsy. Inverse agonists at the serotonin5-HT_(2A) receptor improve the quality of sleep at nightime which candecrease excessive daytime sleepiness.

Accordingly, another aspect of the present invention relates to thetherapeutic use of compounds of the present invention for the treatmentof Sleep Disorders. Compounds of the present invention are potentinverse agonists at the serotonin 5-HT_(2A) receptor and can beeffective in the treatment of Sleep Disorders by promoting one or moreof the following: reducing the sleep onset latency period (measure ofsleep induction), reducing the number of nighttime awakenings, andprolonging the amount of time in delta-wave sleep (measure of sleepquality enhancement and sleep consolidation) without effecting REMsleep. In addition, compounds of the present invention can be effectiveeither as a monotherapy or in combination with sleep inducing agents,for example but not limited to, antihistamines.

6. Diabetic-Related Pathologies:

Although hyperglycemia is the major cause for the pathogenesis ofdiabetic complications such as diabetic peripheral neuropathy (DPN),diabetic nephropathy (DN) and diabetic retinopathy (DR), increasedplasma serotonin concentration in diabetic patients has also beenimplicated to play a role in disease progression (Pietraszek, M. H., etal. Thrombosis Res. 1992, 66(6), 765-74; and Andrzejewska-Buczko J, etal., Klin Oczna. 1996; 98(2), 101-4). Serotonin is believed to play arole in vasospasm and increased platelet aggregability. Improvingmicrovascular blood flow is able to benefit diabetic complications.

A recent study by Cameron and Cotter in Naunyn Schmiedebergs ArchPharmacol. 2003 June; 367(6):607-14, used a 5-HT_(2A) antagonistexperimental drug AT-1015, and other nonspecific 5-HT_(2A) antagonistsincluding ritanserin and sarpogrelate. These studies found that allthree drugs were able to produce a marked correction (82.6-99.7%) of a19.8% sciatic motor conduction deficit in diabetic rats. Similarly,44.7% and 14.9% reductions in sciatic endoneurial blood flow andsaphenous sensory conduction velocity were completely reversed.

In a separate patient study, sarpogrelate was evaluated for theprevention of the development or progression of diabetic nephropathy(Takahashi, T., et al., Diabetes Res Clin Pract. 2002 November;58(2):123-9). In the trial of 24 months of treatment, sarpogrelatesignificantly reduced urinary albumin excretion level.

7. Glaucoma

Topical ocular administration of 5-HT2 receptor antagonists result in adecrease in intra ocular pressure (IOP) in monkeys (Chang et al., J.Ocul Pharmacol 1:137-147 (1985)) and humans (Mastropasqua et al., ActaOphthalmol Scand Suppl 224:24-25 (1997)) indicating utility for similarcompounds such as 5-HT_(2A) inverse agonists in the treatment of ocularhypertension associated with glaucoma. The 5-HT2 receptor antagonistketanserin (Mastropasqua supra) and sarpogrelate (Takenaka et al.,Investig Ophthalmol Vis Sci 36:S734 (1995)) have been shown tosignificantly lower IOP in glaucoma patients.

8. Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a lethaldemyelinating disease caused by an opportunistic viral infection ofoligodendrocytes in immunocompromised patients. The causative agent isJC virus, a ubiquitous papovavirus that infects the majority of thepopulation before adulthood and establishes a latent infection in thekidney. In immunocompromised hosts, the virus can reactivate andproductively infect oligodendrocytes. This previously rare condition,until 1984 reported primarily in persons with underlyinglymphoproliferative disorders, is now more common because it occurs in4% of patients with AIDS. Patients usually present with relentlesslyprogressive focal neurologic defects, such as hemiparesis or visualfield deficits, or with alterations in mental status. On brain MRI, oneor more white matter lesions are present; they are hyperintense onT2-weighted images and hypointense on T1-weighted images. There is nomass effect, and contrast enhancement is rare. Diagnosis can beconfirmed by brain biopsy, with demonstration of virus by in situhybridization or immunocytochemistry. Polymerase chain reactionamplification of JC virus sequences from the CSF can confirm diagnosiswithout the need for biopsy [see, e.g., Antinori et al., Neurology(1997) 48:687-694; Berger and Major, Seminars in Neurology (1999)19:193-200; and Portegies, et al., Eur. J. Neurol. (2004) 11:297-304].Currently, there is no effective therapy. Survival after diagnosis isabout 3 to 5 months in AIDS patients.

JC virus enters cells by receptor-mediated clathrin-dependentendocytosis. Binding of JC virus to human glial cells (e.g.,oligodendrocytes) induces an intracellular signal that is critical forentry and infection by a ligand-inducible clathrin-dependent mechanism[Querbes et al., J Virology (2004) 78:250-256]. Recently, 5-HT_(2A) wasshown to be the receptor on human glial cells mediating infectious entryof JC virus by clathrin-dependent endocytosis [Elphick et al., Science(2004) 306:1380-1383]. 5-HT_(2A) antagonists, including ketanserin andritanserin, inhibited JC virus infection of human glial cells.Ketanserin and ritanserin have inverse agonist activity at 5-HT_(2A).

5-HT_(2A) antagonists including inverse agonists have been contemplatedto be useful in the treatment of PML [Elphick et al., Science (2004)306:1380-1383]. Prophylactic treatment of HIV-infected patients with5-HT_(2A) antagonists is envisioned to prevent the spread of JC virus tothe central nervous system and the development of PML. Aggressivetherapeutic treatment of patients with PML is envisioned to reduce viralspread within the central nervous system and prevent additional episodesof demyelination.

In some embodiments, methods are provided for treating progressivemultifocal leukoencephalopathy in a patient in need of such treatment,comprising administering to the patient a composition comprising a5-HT_(2A) inverse agonist disclosed herein.

9. Hypertension

Serotonin has been observed to play an important role in the regulationof vascular tone, vasoconstriction, and pulmonary hypertension (see,Deuchar, G. et al. Pulm. Pharmacol. Ther. 18(1):23-31. 2005; and Marcos,E. et al. Circ. Res. 94(9):1263-70 2004). Ketanserin, a 5-HT2A inverseagonist, have been demonstrated to protect against circulatory shocks,intracranial hypertension, and cerebral ischemia during heatstroke (see,Chang, C. et al. Shock 24(4): 336-340 2005); and to stabilize bloodpressure in spontaneously hypertensive rats (see, Miao, C. Clin. Exp.Pharmacol. Physiol. 30(3): 189-193). Mainserin, a 5-HT2A inverseagonist, has been shown to prevent DOCA-salt induced hypertension inrats (see, Silva, A. Eur, J. Pharmacol. 518(2-3): 152-7 2005).

10. Pain

5-HT2A inverse agonists are also effective for the treatment of pain.Sarpogrelate has been observed to provide a significant analgesic effectboth on thermal induced pain in rats after intraperitonealadministration and on inflammatory pain in rats after either intrathecalor intraperitoneal administration (see, Nishiyama, T. Eur. J. Pharmacol.516:18-22 2005). This same 5-HT2A inverse agonist in humans has beenshown to be an effective treatment for lower back pain, leg pain andnumbness associated with sciatica brought on by lumbar disc herniation(see, Kanayama, M. et al. J. Neurosurg: Spine 2:441-446 2005).

Representative Methods of the Invention:

One aspect of the present invention pertains to methods for modulatingthe activity of a 5-HT_(2A) serotonin receptor by contacting thereceptor with a compound according to any of the embodiments describedherein or a pharmaceutical composition.

One aspect of the present invention pertains to methods for thetreatment of platelet aggregation in an individual comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a compound according to any of the embodimentsdescribed herein or a pharmaceutical composition.

One aspect of the present invention pertains to methods for thetreatment of an indication selected from the group consisting ofcoronary artery disease, myocardial infarction, transient ischemicattack, angina, stroke, and atrial fibrillation in an individualcomprising administering to the individual in need thereof atherapeutically effective amount of a compound according to any of theembodiments described herein or a pharmaceutical composition.

One aspect of the present invention pertains to methods for reducing therisk of blood clot formation in an angioplasty or coronary bypasssurgery individual comprising administering to the individual in needthereof a therapeutically effective amount of a compound according toany of the embodiments described herein or a pharmaceutical composition.

One aspect of the present invention pertains to methods for reducing therisk of blood clot formation in an individual suffering from atrialfibrillation, comprising administering to the individual in need thereofa therapeutically effective amount of a compound according to any of theembodiments described herein or a pharmaceutical composition.

One aspect of the present invention pertains to methods for thetreatment of asthma in an individual comprising administering to theindividual in need thereof a therapeutically effective amount of acompound according to any of the embodiments described herein or apharmaceutical composition.

One aspect of the present invention pertains to methods for thetreatment of a symptom of asthma in an individual comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a compound according to any of the embodimentsdescribed herein or a pharmaceutical composition.

One aspect of the present invention pertains to methods for thetreatment of agitation or a symptom thereof in an individual comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a compound according to any of the embodimentsdescribed herein or a pharmaceutical composition. In some embodiments,the individual is a cognitively intact elderly individual.

One aspect of the present invention pertains to methods for thetreatment of agitation or a symptom thereof in an individual sufferingfrom dementia comprising administering to the individual in need thereofa therapeutically effective amount of a compound according to any of theembodiments described herein or a pharmaceutical composition. In someembodiments, the dementia is due to a degenerative disease of thenervous system. In some embodiments, the dementia is Alzheimers disease,Lewy body, Parkinson's disease or Huntington's disease. In someembodiments, the dementia is due to diseases that affect blood vessels.In some embodiments, the dementia is due to stroke or multi-infarctdementia.

One aspect of the present invention pertains to methods for thetreatment of an individual suffering from at least one of theindications selected from the group consisting of behavioral disorder,drug induced psychosis, excitative psychosis, Gilles de la Tourette'ssyndrome, manic disorder, organic or NOS psychosis, psychotic disorder,psychosis, acute schizophrenia, chronic schizophrenia and NOSschizophrenia comprising administering to the individual in need thereofa therapeutically effective amount of a dopamine D₂ receptor antagonistand a compound according to any of the embodiments described herein or apharmaceutical composition. In some embodiments, the dopamine D₂receptor antagonist is haloperidol.

One aspect of the present invention pertains to methods for thetreatment of an individual with infantile autism, Huntington's chorea,or nausea and vomiting from chemotherapy or chemotherapeutic antibodiescomprising administering to the individual in need thereof atherapeutically effective amount of a dopamine D₂ receptor antagonistand a compound according to any of the embodiments described herein or apharmaceutical composition. In some embodiments, the dopamine D₂receptor antagonist is haloperidol.

One aspect of the present invention pertains to methods for thetreatment of schizophrenia in an individual comprising administering tothe individual in need thereof a therapeutically effective amount of adopamine D₂ receptor antagonist and a compound according to any of theembodiments described herein or a pharmaceutical composition. In someembodiments, the dopamine D₂ receptor antagonist is haloperidol.

One aspect of the present invention pertains to methods for thetreatment of alleviating negative symptoms of schizophrenia induced bythe administration of haloperidol to an individual suffering from theschizophrenia, comprising administering to the individual in needthereof a therapeutically effective amount of a compound according toany of the embodiments described herein or a pharmaceutical composition.In some embodiments, the haloperidol and the compound or pharmaceuticalcomposition are administered in separate dosage forms. In someembodiments, the haloperidol and the compound or pharmaceuticalcomposition are administered in a single dosage form.

One aspect of the present invention pertains to methods for thetreatment of a sleep disorder in an individual comprising administeringto the individual in need thereof a therapeutically effective amount ofa compound according to any of the embodiments described herein or apharmaceutical composition.

In some embodiments, the sleep disorder is a dyssomnia. In someembodiments, the dyssomnia is selected from the group consisting ofpsychophysiological insomnia, sleep state misperception, idiopathicinsomnia, obstructive sleep apnea syndrome, central sleep apneasyndrome, central alveolar hypoventilation syndrome, periodic limbmovement disorder, restless leg syndrome, inadequate sleep hygiene,environmental sleep disorder, altitude insomnia, adjustment sleepdisorder, insufficient sleep syndrome, limit-setting sleep disorder,sleep-onset association disorder, nocturnal eating or drinking syndrome,hypnotic dependent sleep disorder, stimulant-dependent sleep disorder,alcohol-dependent sleep disorder, toxin-induced sleep disorder, timezone change (jet lag) syndrome, shift work sleep disorder, irregularsleep-wake pattern, delayed sleep phase syndrome, advanced sleep phasesyndrome, and non-24-hour sleep-wake disorder.

In some embodiments, the sleep disorder is a parasomnia. In someembodiments, the parasomnia is selected from the group consisting ofconfusional arousals, sleepwalking and sleep terrors, rhythmic movementdisorder, sleep starts, sleep talking and nocturnal leg cramps. In someembodiments, the sleep disorder is characterized by excessive daytimesleepiness such as narcolepsy.

In some embodiments, the sleep disorder is associated with a medical orpsychiatric disorder. In some embodiments, the medical or psychiatricdisorder is selected from the group consisting of psychoses, mooddisorders, anxiety disorders, panic disorders, alcoholism, cerebraldegenerative disorders, dementia, parkinsonism, fatal familial insomnia,sleep-related epilepsy, electrical status epilepticus of sleep,sleep-related headaches, sleeping sickness, nocturnal cardiac ischemia,chronic obstructive pulmonary disease, sleep-related asthma,sleep-related gastroesophageal reflux, peptic ulcer disease, fibrositissyndrome, osteoarthritis, rheumatoid arthritis, fibromyalgia andpost-surgical sleep disorder.

One aspect of the present invention pertains to methods for thetreatment of a diabetic-related disorder in an individual comprisingadministering to the individual in need thereof a therapeuticallyeffective amount of a compound according to any of the embodimentsdescribed herein or a pharmaceutical composition.

In some embodiments, the diabetic-related disorder is diabeticperipheral neuropathy.

In some embodiments, the diabetic-related disorder is diabeticnephropathy.

In some embodiments, the diabetic-related disorder is diabeticretinopathy.

One aspect of the present invention pertains to methods for thetreatment of glaucoma or other diseases of the eye with abnormalintraocular pressure.

One aspect of the present invention pertains to methods for thetreatment of progressive multifocal leukoencephalopathy in an individualcomprising administering to the individual in need thereof atherapeutically effective amount of a compound according to any of theembodiments described herein or a pharmaceutical composition.

In some embodiments, the individual in need thereof has alymphoproliferative disorder. In some embodiments, thelymphoproliferative disorder is leukemia or lymphoma. In someembodiments, the leukemia or lymphoma is chronic lymphocytic leukemia,Hodgkin's disease, or the like.

In some embodiments, the individual in need thereof has amyeloproliferative disorder.

In some embodiments, the individual in need thereof has carcinomatosis.

In some embodiments, the individual in need thereof has a granulomatousor inflammatory disease. In some embodiments, the granulomatous orinflammatory disease is tuberculosis or sarcoidosis.

In some embodiments, the individual in need thereof isimmunocompromised. In some embodiments, the immunocompromised individualhas impaired cellular immunity. In some embodiments, the impairedcellular immunity comprises impaired T-cell immunity.

In some embodiments, the individual in need thereof is infected withHIV. In some embodiments, the HIV-infected individual has a CD4+ cellcount of ≤200/mm³. In some embodiments, the HIV-infected individual hasAIDS. In some embodiments, the HIV-infected individual has AIDS-relatedcomplex (ARC). In certain embodiments, ARC is defined as the presence oftwo successive CD4+ cell counts below 200/mm³ and at least two of thefollowing signs or symptoms: oral hairy leukoplakia, recurrent oralcandidiasis, weight loss of at least 2.5 kg or 10% of body weight withinlast six months, multidermatomal herpes zoster, temperature above 38.5°C. for more than 14 consecutive days or more than 15 days in a 30-dayperiod, or diarrhea with more than three liquid stools per day for atleast 30 days [see, e.g., Yamada et al., Clin. Diagn. Virol. (1993)1:245-256].

In some embodiments, the individual in need thereof is undergoingimmunosuppressive therapy. In some embodiments, the immunosuppressivetherapy comprises administering an immunosuppressive agent [see, e.g.,Mueller, Ann Thorac Surg (2004) 77:354-362; and Krieger and Emre,Pediatr Transplantation (2004) 8:594-599]. In some embodiments, theimmunosuppressive therapy comprises administering an immunosuppressiveagent selected from the group consisting of: corticosteroids (forexample, prednisone and the like), calcineurin inhibitors (for example,cyclosporine, tacrolimus, and the like), antiproliferative agents (forexample, azathioprine, mycophenolate mofetil, sirolimus, everolimus, andthe like), T-cell depleting agents (for example, OKT®3 monoclonalantibody (mAb), anti-CD3 immunotoxin FN18-CRM9, Campath-1H (anti-CD52)mAb, anti-CD4 mAb, anti-T cell receptor mAb, and the like), anti-IL-2receptor (CD25) mAb (for example, basiliximab, daclizumab, and thelike), inhibitors of co-stimulation (for example, CTLA4-Ig, anti-CD154(CD40 ligand) mAb, and the like), deoxyspergualin and analogs thereof(for example, 15-DSG, LF-08-0299, LF14-0195, and the like), leflunomideand analogs thereof (for example, leflunomide, FK778, FK779, and thelike), FTY720, anti-alpha-4-integrin monoclonal antibody, and anti-CD45RB monoclonal antibody. In some embodiments, the immunosuppressive agentand the compound or pharmaceutical composition are administered inseparate dosage forms. In some embodiments, the immunosuppressive agentand the compound or pharmaceutical composition are administered in asingle dosage form.

In some embodiments, the individual in need thereof is undergoingimmunosuppressive therapy after organ transplantation. In someembodiments, the organ is liver, kidney, lung, heart, or the like [see,e.g., Singh et al., Transplantation (2000) 69:467-472].

In some embodiments, the individual in need thereof is undergoingtreatment for a rheumatic disease. In some embodiments, the rheumaticdisease is systemic lupus erythematosus or the like.

In some embodiments, the compound or the pharmaceutical compositioninhibits JC virus infection of human glial cells.

One aspect of the present invention encompasses processes for preparinga composition comprising admixing a compound according any embodimentsdescribed herein and a pharmaceutically acceptable carrier.

One aspect of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the disorder is platelet aggregation.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the disorder is selected from the groupconsisting of coronary artery disease, myocardial infarction, transientischemic attack, angina, stroke, and atrial fibrillation.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the disorder is a blood clot formation in anangioplasty or coronary bypass surgery individual.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the disorder is a blood clot formation in anindividual suffering from atrial fibrillation.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the disorder is asthma.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the disorder is a symptom of asthma.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the disorder is agitation or a symptomthereof in an individual. In some embodiments the individual is acognitively intact elderly individual.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the disorder is agitation or a symptomthereof in an individual suffering from dementia. In some embodimentsthe dementia is due to a degenerative disease of the nervous system. Insome embodiment the dementia is Alzheimers disease, Lewy body,Parkinson's disease, or Huntington's disease. In some embodiments thedementia is due to diseases that affect blood vessels. In someembodiments the dementia is due to stroke or multi-infract dementia.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder further comprising a dopamine D₂ receptor antagonistwherein the disorder is selected from the group consisting of abehavioral disorder, drug induced psychosis, excitative psychosis,Gilles de la Tourette's syndrome, manic disorder, organic or NOSpsychosis, psychotic disorder, psychosis, acute schizophrenia, chronicschizophrenia and NOS schizophrenia. In some embodiments the dopamine D₂receptor antagonist is haloperidol.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder further comprising a dopamine D₂ receptor antagonistwherein the disorder is infantile autism, Huntington's chorea, or nauseaand vomiting from chemotherapy or chemotherapeutic antibodies. In someembodiments the dopamine D₂ receptor antagonist is haloperidol.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder further comprising a dopamine D₂ receptor antagonistwherein the disorder is schizophrenia. In some embodiments the dopamineD₂ receptor antagonist is haloperidol.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the disorder is a negative symptom orsymptoms of schizophrenia induced by the administration of haloperidol.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the haloperidol and the compound orpharmaceutical composition are administered in separate dosage forms.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the haloperidol and the compound orpharmaceutical composition are administered in a single dosage form.

One embodiment of the present invention is the use of a compound for theproduction of a medicament for use in the treatment of a 5-HT_(2A)associated disorder wherein the disorder is progressive multifocalleukoencephalopathy.

One aspect of the present invention are compounds according to any ofthe embodiments described herein for use in a method of treatment of thehuman or animal body by therapy.

One aspect of the present invention are compounds according to any ofthe embodiments described herein for use in a method for the treatmentof a 5-HT_(2A) associated disorder, as described herein, in the human oranimal body by therapy.

One aspect of the present invention are compounds according to any ofthe embodiments described herein for use in a method for the treatmentof a sleep disorder, as described herein, in the human or animal body bytherapy.

One aspect of the present invention are compounds according to any ofthe embodiments described herein for use in a method for the treatmentof platelet aggregation in the human or animal body by therapy.

One aspect of the present invention are compounds according to any ofthe embodiments described herein for use in a method for the treatmentof progressive multifocal leukoencephalopathy in the human or animalbody by therapy.

Pharmaceutical Compositions

A further aspect of the present invention pertains to pharmaceuticalcompositions comprising one or more compounds as described herein andone or more pharmaceutically acceptable carriers. Some embodimentspertain to pharmaceutical compositions comprising a compound of thepresent invention and a pharmaceutically acceptable carrier.

Some embodiments of the present invention include a method of producinga pharmaceutical composition comprising admixing at least one compoundaccording to any of the compound embodiments disclosed herein and apharmaceutically acceptable carrier.

Formulations may be prepared by any suitable method, typically byuniformly mixing the active compound(s) with liquids or finely dividedsolid carriers, or both, in the required proportions, and then, ifnecessary, forming the resulting mixture into a desired shape.

Conventional excipients, such as binding agents, fillers, acceptablewetting agents, tabletting lubricants, and disintegrants may be used intablets and capsules for oral administration. Liquid preparations fororal administration may be in the form of solutions, emulsions, aqueousor oily suspensions, and syrups. Alternatively, the oral preparationsmay be in the form of dry powder that can be reconstituted with water oranother suitable liquid vehicle before use. Additional additives such assuspending or emulsifying agents, non-aqueous vehicles (including edibleoils), preservatives, and flavorings and colorants may be added to theliquid preparations. Parenteral dosage forms may be prepared bydissolving the compound of the invention in a suitable liquid vehicleand filter sterilizing the solution before filling and sealing anappropriate vial or ampoule. These are just a few examples of the manyappropriate methods well known in the art for preparing dosage forms.

A compound of the present invention can be formulated intopharmaceutical compositions using techniques well known to those in theart. Suitable pharmaceutically-acceptable carriers, outside thosementioned herein, are known in the art; for example, see Remington. TheScience and Practice of Pharmacy, 20th Edition, 2000, LippincottWilliams & Wilkins, (Editors: Gennaro, A. R., et al).

While it is possible that, for use in the treatment, a compound of theinvention may, in an alternative use, be administered as a raw or purechemical, it is preferable however to present the compound or activeingredient as a pharmaceutical formulation or composition furthercomprising a pharmaceutically acceptable carrier.

The invention thus further provides pharmaceutical formulationscomprising a compound of the invention or a pharmaceutically acceptablesalt or derivative thereof together with one or more pharmaceuticallyacceptable carriers thereof and/or prophylactic ingredients. Thecarrier(s) must be “acceptable” in the sense of being compatible withthe other ingredients of the formulation and not overly deleterious tothe recipient thereof.

Pharmaceutical formulations include those suitable for oral, rectal,nasal, topical (including buccal and sub-lingual), vaginal or parenteral(including intramuscular, subcutaneous and intravenous) administrationor in a form suitable for administration by inhalation, insufflation orby a transdermal patch. Transdermal patches dispense a drug at acontrolled rate by presenting the drug for absorption in an efficientmanner with a minimum of degradation of the drug. Typically, transdermalpatches comprise an impermeable backing layer, a single pressuresensitive adhesive and a removable protective layer with a releaseliner. One of ordinary skill in the art will understand and appreciatethe techniques appropriate for manufacturing a desired efficacioustransdermal patch based upon the needs of the artisan.

The compounds of the invention, together with a conventional adjuvant,carrier, or diluent, may thus be placed into the form of pharmaceuticalformulations and unit dosages thereof, and in such form may be employedas solids, such as tablets or filled capsules, or liquids such assolutions, suspensions, emulsions, elixirs, gels or capsules filled withthe same, all for oral use, in the form of suppositories for rectaladministration; or in the form of sterile injectable solutions forparenteral (including subcutaneous) use. Such pharmaceuticalcompositions and unit dosage forms thereof may comprise conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and such unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed.

For oral administration, the pharmaceutical composition may be in theform of, for example, a tablet, capsule, suspension or liquid. Thepharmaceutical composition is preferably made in the form of a dosageunit containing a particular amount of the active ingredient. Examplesof such dosage units are capsules, tablets, powders, granules or asuspension, with conventional additives such as lactose, mannitol, cornstarch or potato starch; with binders such as crystalline cellulose,cellulose derivatives, acacia, corn starch or gelatins; withdisintegrators such as corn starch, potato starch or sodiumcarboxymethyl-cellulose; and with lubricants such as talc or magnesiumstearate. The active ingredient may also be administered by injection asa composition wherein, for example, saline, dextrose or water may beused as a suitable pharmaceutically acceptable carrier.

Compounds of the present invention or a solvate or physiologicallyfunctional derivative thereof can be used as active ingredients inpharmaceutical compositions, specifically as 5-HT_(2A) receptormodulators. By the term “active ingredient” is defined in the context ofa “pharmaceutical composition” and shall mean a component of apharmaceutical composition that provides the primary pharmacologicaleffect, as opposed to an “inactive ingredient” which would generally berecognized as providing no pharmaceutical benefit.

The dose when using the compounds of the present invention can varywithin wide limits, as is customary and is known to the physician, it isto be tailored to the individual conditions in each individual case. Itdepends, for example, on the nature and severity of the illness to betreated, on the condition of the patient, on the compound employed or onwhether an acute or chronic disease state is treated or prophylaxis isconducted or on whether further active compounds are administered inaddition to the compounds of the present invention. Representative dosesof the present invention include, but are not limited to, about 0.001 mgto about 5000 mg, about 0.001 mg to about 2500 mg, about 0.001 mg toabout 1000 mg, 0.001 mg to about 500 mg, 0.001 mg to about 250 mg, about0.001 mg to 100 mg, about 0.001 mg to about 50 mg, and about 0.001 mg toabout 25 mg. Multiple doses may be administered during the day,especially when relatively large amounts are deemed to be needed, forexample 2, 3 or 4, doses. Depending on the individual and as deemedappropriate from the patient's physician or care-giver it may benecessary to deviate upward or downward from the doses described herein.

The amount of active ingredient, or an active salt or derivativethereof, required for use in treatment will vary not only with theparticular salt selected but also with the route of administration, thenature of the condition being treated and the age and condition of thepatient and will ultimately be at the discretion of the attendantphysician or clinician. In general, one skilled in the art understandshow to extrapolate in vivo data obtained in a model system, typically ananimal model, to another, such as a human. In some circumstances, theseextrapolations may merely be based on the weight of the animal model incomparison to another, such as a mammal, preferably a human, however,more often, these extrapolations are not simply based on weights, butrather incorporate a variety of factors. Representative factors includethe type, age, weight, sex, diet and medical condition of the patient,the severity of the disease, the route of administration,pharmacological considerations such as the activity, efficacy,pharmacokinetic and toxicology profiles of the particular compoundemployed, whether a drug delivery system is utilized, or whether anacute or chronic disease state is being treated or prophylaxis isconducted or on whether further active compounds are administered inaddition to the compounds of the present invention and as part of a drugcombination. The dosage regimen for treating a disease condition withthe compounds and/or compositions of this invention is selected inaccordance with a variety factors as cited above. Thus, the actualdosage regimen employed may vary widely and therefore may deviate from apreferred dosage regimen and one skilled in the art will recognize thatdosage and dosage regimen outside these typical ranges can be testedand, where appropriate, may be used in the methods of this invention.

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of discrete loosely spacedadministrations. The daily dose can be divided, especially whenrelatively large amounts are administered as deemed appropriate, intoseveral, for example 2, 3 or 4, part administrations. If appropriate,depending on individual behavior, it may be necessary to deviate upwardor downward from the daily dose indicated.

The compounds of the present invention can be administrated in a widevariety of oral and parenteral dosage forms. It will be obvious to thoseskilled in the art that the following dosage forms may comprise, as theactive component, either a compound of the invention or apharmaceutically acceptable salt of a compound of the invention.

For preparing pharmaceutical compositions from the compounds of thepresent invention, the selection of a suitable pharmaceuticallyacceptable carrier can be either solid, liquid or a mixture of both.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier can beone or more substances which may also act as diluents, flavouringagents, solubilizers, lubricants, suspending agents, binders,preservatives, tablet disintegrating agents, or an encapsulatingmaterial.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding capacity in suitable proportions and compacted to thedesire shape and size.

The powders and tablets may contain varying percentage amounts of theactive compound. A representative amount in a powder or tablet maycontain from 0.5 to about 90 percent of the active compound; however, anartisan would know when amounts outside of this range are necessary.Suitable carriers for powders and tablets are magnesium carbonate,magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch,gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, alow melting wax, cocoa butter, and the like. The term “preparation” isintended to include the formulation of the active compound withencapsulating material as carrier providing a capsule in which theactive component, with or without carriers, is surrounded by a carrier,which is thus in association with it. Similarly, cachets and lozengesare included. Tablets, powders, capsules, pills, cachets, and lozengescan be used as solid forms suitable for oral administration.

For preparing suppositories, a low melting wax, such as an admixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or sprays containing inaddition to the active ingredient such carriers as are known in the artto be appropriate.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water-propylene glycol solutions. For example,parenteral injection liquid preparations can be formulated as solutionsin aqueous polyethylene glycol solution. Injectable preparations, forexample, sterile injectable aqueous or oleaginous suspensions may beformulated according to the known art using suitable dispersing orwetting agents and suspending agents. The sterile injectable preparationmay also be a sterile injectable solution or suspension in a nontoxicparenterally acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are water, Ringer's solution, and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables.

The compounds according to the present invention may thus be formulatedfor parenteral administration (e.g. by injection, for example bolusinjection or continuous infusion) and may be presented in unit dose formin ampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers with an added preservative. The pharmaceutical compositionsmay take such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilization from solution, for constitution witha suitable vehicle, e.g. sterile, pyrogen-free water, before use.

Aqueous formulations suitable for oral use can be prepared by dissolvingor suspending the active component in water and adding suitablecolorants, flavours, stabilizing and thickening agents, as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, or other well known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

For topical administration to the epidermis the compounds according tothe invention may be formulated as ointments, creams or lotions, or as atransdermal patch.

Ointments and creams may, for example, be formulated with an aqueous oroily base with the addition of suitable thickening and/or gellingagents. Lotions may be formulated with an aqueous or oily base and willin general also contain one or more emulsifying agents, stabilizingagents, dispersing agents, suspending agents, thickening agents, orcoloring agents.

Formulations suitable for topical administration in the mouth includelozenges comprising active agent in a flavored base, usually sucrose andacacia or tragacanth; pastilles comprising the active ingredient in aninert base such as gelatin and glycerin or sucrose and acacia; andmouthwashes comprising the active ingredient in a suitable liquidcarrier.

Solutions or suspensions are applied directly to the nasal cavity byconventional means, for example with a dropper, pipette or spray. Theformulations may be provided in single or multi-dose form. In the lattercase of a dropper or pipette, this may be achieved by the patientadministering an appropriate, predetermined volume of the solution orsuspension. In the case of a spray, this may be achieved for example bymeans of a metering atomizing spray pump.

Administration to the respiratory tract may also be achieved by means ofan aerosol formulation in which the active ingredient is provided in apressurized pack with a suitable propellant. If the compounds of thepresent invention or pharmaceutical compositions comprising them areadministered as aerosols, for example as nasal aerosols or byinhalation, this can be carried out, for example, using a spray, anebulizer, a pump nebulizer, an inhalation apparatus, a metered inhaleror a dry powder inhaler. Pharmaceutical forms for administration of thecompounds of the present invention as an aerosol can be prepared byprocesses well-known to the person skilled in the art. For theirpreparation, for example, solutions or dispersions of the compounds ofthe present invention in water, water/alcohol mixtures or suitablesaline solutions can be employed using customary additives, for examplebenzyl alcohol or other suitable preservatives, absorption enhancers forincreasing the bioavailability, solubilizers, dispersants and others,and, if appropriate, customary propellants, for example include carbondioxide, CFC's, such as, dichlorodifluoromethane,trichlorofluoromethane, or dichlorotetrafluoroethane; and the like. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by provision of a metered valve.

In formulations intended for administration to the respiratory tract,including intranasal formulations, the compound will generally have asmall particle size for example of the order of 10 microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. When desired, formulations adapted to give sustainedrelease of the active ingredient may be employed.

Alternatively the active ingredients may be provided in the form of adry powder, for example, a powder mix of the compound in a suitablepowder base such as lactose, starch, starch derivatives such ashydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).Conveniently the powder carrier will form a gel in the nasal cavity. Thepowder composition may be presented in unit dose form for example incapsules or cartridges of, e.g., gelatin, or blister packs from whichthe powder may be administered by means of an inhaler.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Tablets or capsules for oral administration and liquids for intravenousadministration are preferred compositions.

The compounds according to the invention may optionally exist aspharmaceutically acceptable salts including pharmaceutically acceptableacid addition salts prepared from pharmaceutically acceptable non-toxicacids including inorganic and organic acids. Representative acidsinclude, but are not limited to, acetic, benzenesulfonic, benzoic,camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic,fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfiric,tartaric, oxalic, p-toluenesulfonic and the like, such as thosepharmaceutically acceptable salts listed in Journal of PharmaceuticalScience, 66, 2 (1977); incorporated herein by reference in its entirety.

The acid addition salts may be obtained as the direct products ofcompound synthesis. In the alternative, the free base may be dissolvedin a suitable solvent containing the appropriate acid, and the saltisolated by evaporating the solvent or otherwise separating the salt andsolvent. The compounds of this invention may form solvates with standardlow molecular weight solvents using methods known to the skilledartisan.

Some embodiments of the present invention include a method of producinga pharmaceutical composition for “combination-therapy” comprisingadmixing at least one compound according to any of the compoundembodiments disclosed herein, together with at least one knownpharmaceutical agent as described herein and a pharmaceuticallyacceptable carrier.

It is noted that when the 5-HT_(2A) receptor modulators are utilized asactive ingredients in a pharmaceutical composition, these are notintended for use only in humans, but in other non-human mammals as well.Indeed, recent advances in the area of animal health-care mandate thatconsideration be given for the use of active agents, such as 5-HT_(2A)receptor modulators, for the treatment of a 5-HT_(2A) mediated diseaseor disorder in domestic animals (e.g., cats and dogs) and in otherdomestic animals (e.g., such as cows, chickens, fish, etc.). Those ofordinary skill in the art are readily credited with understanding theutility of such compounds in such settings.

Combination Therapy:

While the compounds of the present invention can be administered as thesole active pharmaceutical agent (i.e., mono-therapy), they can also beused in combination with other pharmaceutical agents (i.e.,combination-therapy) for the treatment of thediseases/conditions/disorders described herein. Accordingly, anotheraspect of the present invention includes methods of treatment of5-HT_(2A) serotonin receptor associated disorders diseases comprisingadministering to an individual in need of such treatment atherapeutically-effective amount of a compound of the present inventionin combination with one or more additional pharmaceutical agent asdescribed herein.

Suitable pharmaceutical agents that can be used in combination with thecompounds of the present invention include other antiplatelet,antithrombotic or anticoagulant drugs, anti-arrhythmic agents,Cholesteryl ester transfer protein (CETP) inhibitors, Niacin or niacinanalogs, Adenosine or adenosine analogs, Nitroglycerin or nitrates,prothrombolytic agents, and the like. Other pharmaceutical agents,including the agents set forth infra, are well known or will be readilyapparent in light of the instant disclosure, to one of ordinary skill inthe art.

The compounds of the present invention can also be used in combinationwith other antiplatelet, antithrombotic or anticoagulant drugs such asthrombin inhibitors, platelet aggregation inhibitors such as aspirin,clopidogrel (Plavix®), ticlopidine or CS-747 {i.e., acetic acid5-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-ylester and its active metabolite R-99224,(Z)-2-[1-[2-cyclopropyl-1(S)-(2-fluorophenyl)-2-oxoethyl]-4(R)-sulfanylpiperidin-3-ylidene]aceticacid}, abciximab (ReoPro®), eptifibatide (Integrilin®), tirofiban(Aggrastat®), warfarin, low molecular weight heparins (such as LOVENOX),GPIIb/GPIIIa blockers, PAI-1 inhibitors such as XR-330 [i.e.,(3Z,6Z)-3-Benzylidene-6-(4-methoxybenzylidene)-1-methylpiperazine-2,5-dione]and T-686 [i.e.,3(E)-Benzylidene-4(E)-(3,4,5-trimethoxybenzylidene)pyrrolidine-2,5-dione],inhibitors of α-2-antiplasmin such as anti-α-2-antiplasmin antibody andthromboxane receptor antagonists (such as ifetroban), prostacyclinmimetics, phosphodiesterase (PDE) inhibitors, such as dipyridamole(Persantine®) or cilostazol, PDE inhibitors in combination withthromboxane receptor antagonists/thromboxane A synthetase inhibitors(such as picotamide), serotonin-2-receptor antagonists (such asketanserin), fibrinogen receptor antagonists, hypolipidemic agents, suchas HMG-CoA reductase inhibitors, e.g., pravastatin, simvastatin,atorvastatin, fluvastatin, cerivastatin, AZ4522, and itavastatin(Nissan/Kowa); microsomal triglyceride transport protein inhibitors(such as disclosed in U.S. Pat. Nos. 5,739,135, 5,712,279 and5,760,246), antihypertensive agents such as angiotensin-convertingenzyme inhibitors (e.g., captopril, lisinopril or fosinopril);angiotensin-II receptor antagonists (e.g., irbesartan, losartan orvalsartan); and/or ACE/NEP inhibitors (e.g., omapatrilat andgemopatrilat); β-blockers (such as propranolol, nadolol and carvedilol),PDE inhibitors in combination with aspirin, ifetroban, picotamide,ketanserin, or clopidogrel (Plavix®) and the like.

The compound of the present invention can also be used in combinationwith anti-arrhythmic agents such as for atrial fibrillation, forexample, amiodarone or dofetilide.

The compound of the present invention can also be used in combinationwith Cholesteryl ester transfer protein (CETP) inhibitors fordislipidemia and atherosclerosis, Niacin or niacin analogs fordislipidemia and atherosclerosis, Adenosine or adenosine analogs forvasodilation, Nitroglycerin or nitrates for vasodilation.

The compounds of the present invention can be used in combination withprothrombolytic agents, such as tissue plasminogen activator (natural orrecombinant), streptokinase, reteplase, activase, lanoteplase,urokinase, prourokinase, anisolated streptokinase plasminogen activatorcomplex (ASPAC), animal salivary gland plasminogen activators, and thelike. The compounds of the present invention may also be used incombination with β-adrenergic agonists such as albuterol, terbutaline,formoterol, salmeterol, bitolterol, pilbuterol, or fenoterol;anticholinergics such as ipratropium bromide; anti-inflammatorycortiocosteroids such as beclomethasone, triamcinolone, budesonide,fluticasone, flunisolide or dexamethasone; and anti-inflammatory agentssuch as cromolyn, nedocromil, theophylline, zileuton, zafirlukast,monteleukast and pranleukast.

Suitable pharmaceutical agents that can be used in combination withcompounds of the present invention include antiretrovirals [see, e.g.,Turpin, Expert Rev Anti Infect Ther (2003) 1:97-128]. Some embodimentsof the present invention include methods of treatment of progressivemultifocal leukoencephalopathy as described herein comprisingadministering to an individual in need of such treatment atherapeutically effective amount or dose of a compound of the presentinvention in combination with at least one pharmaceutical agent selectedfrom the group consisting of: nucleoside reverse transcriptaseinhibitors (for example, Retrovir®, Epivir®, Combivir®, Hivid®, Videx®,Trizvir®, Zerit®, Ziagen®, Vired®, Emtricitabine, DAPD, and the like),non-nucleoside reverse transcriptase inhibitors (for example,Virammune®, Rescriptor®, Sustiva®, GW687, DPC083, TMC 125, Emivirine,Capravirine, BMS 561390, UC-781 and other oxathiin carboxyanilides,SJ-3366, Alkenyldiarylmethane (ADAM), Tivirapine, Calanolide A, HBY097,Loviride, HEPT Family Derivatives, TIBO Derivatives, and the like),protease inhibitors (for example, Fortovase®, Invirase®, Novir®,Crixivan®, Viracep®, Ageberase®, Kaletra®, Atazanavir, Tipranavir,DMP450, and the like), inhibitors of HIV-cell interaction (for example,soluble CD4, toxin-conjugated CD4, monoclonal antibodies to CD4 orgp120, PRO 542, dextran sulfate, Rersobene, FP-23199, Cyanovirin-N,Zintevir (T30177, AR177), L-chicoric acid and derivatives, and thelike), coreceptor inhibitors ligands (for example, R5, X4, modifiedligands (R5), modified ligands (X4), and the like), coreceptorinhibitors X4 (for example, T22, T134, ALX40-4C, AMD3100, bycyclamderivatives, and the like), coreceptor inhibitors R5 (for example,TAK-779, SCH-C (SCH-351125), SCH-D (SCH-350634), NSC 651016, ONOPharmaceutical, Merck, and the like), fusion inhibitors (for example,Fuzeon® (T-20, DP 178, enfuvritide) trimeris, T-1249, TMC 125, and thelike), integrase inhibitors (for example, 5CITEP, L731,988, L708,906,L-870,812, S-1360, and the like), NCp7 nucleocapsid Zn finger inhibitors(for example, NOBA, DIBA, dithianes, PD-161374, pyridinioalkanoylthioesters (PATES), azodicarbonamide (ADA), cyclic 2,2 dithiobisbenzamide, and the like), RNase H inhibitors (for example, BBHN, CPHMPD-26388, and the like), Tat inhibitors (for example, dominant negativemutants, Ro24-7429, Ro5-3335, and the like), Rev inhibitors (forexample, dominant negative mutants, Leptomycin B, PKF050-638, and thelike), transcriptional inhibitors (for example, Temacrazine, K-12 andK-37, EM2487, and the like), inhibitors of HIV assembly/maturation (forexample, CAP-1 and CAP-2, and the like), and pharmaceutical agentsdirected to cellular anti-HIV targets (for example, LB6-B275 andHRM1275, Cdk9 inhibitors, and the like).

In a certain embodiment, a compound of the invention can be used inconjunction with highly active antiretroviral therapy (HAART). Whenantiretroviral drugs are used in combinations of three or four drugs,this treatment is called HAART [see, e.g., Portegies, et al., Eur. J.Neurol. (2004) 11:297-304].

In accordance with the present invention, the combination of a compoundof the present invention and pharmaceutical agent can be prepared bymixing the respective active components either all together orindependently with a pharmaceutically acceptable carrier, excipient,binder, diluent, etc. as described herein, and administering the mixtureor mixtures either orally or non-orally as a pharmaceuticalcomposition(s). When a compound or a mixture of compounds of Formula(Ia) are administered as a combination therapy with another activecompound each can be formulated as separate pharmaceutical compositionsgiven at the same time or at different times. Alternatively, in someembodiments, pharmaceutical compositions of the present inventioncomprise a compound or a mixture of compounds of Formula (Ia) and thepharmaceutical agent(s) as a single pharmaceutical composition.

Other Utilities

Another object of the present invention relates to radio-labeledcompounds of the present invention that would be useful not only inradio-imaging but also in assays, both in vitro and in vivo, forlocalizing and quantitating the 5-HT_(2A) receptor in tissue samples,including human, and for identifying 5-HT_(2A) receptor ligands byinhibition binding of a radio-labeled compound. It is a further objectof this invention to develop novel 5-HT_(2A) receptor assays of whichcomprise such radio-labeled compounds.

The present invention embraces isotopically-labeled compounds of thepresent invention. An “isotopically” or “radio-labeled” compounds arethose which are identical to compounds disclosed herein, but for thefact that one or more atoms are replaced or substituted by an atomhaving an atomic mass or mass number different from the atomic mass ormass number typically found in nature (i.e., naturally occurring).Suitable radionuclides that may be incorporated in compounds of thepresent invention include, but are not limited to, ²H (also written as Dfor deuterium), ³H (also written as T for tritium), C, ¹³C, ¹⁴C, ¹³N,¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ¹⁸F, ³⁵S, ³⁶Cl, ⁸²Br, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ¹²³I, ¹²⁴I,¹²⁵I and ¹³¹I. The radionuclide that is incorporated in the instantradio-labeled compounds will depend on the specific application of thatradio-labeled compound. For example, for in vitro 5-HT_(2A) receptorlabeling and competition assays, compounds that incorporate ³H, ¹⁴C,⁸²Br, ¹²⁵I, ¹³¹I, ³⁵S or will generally be most useful. Forradio-imaging applications ¹¹C, ¹⁸F, ¹²⁵I, ¹²³I, ¹²⁴I, ¹³¹I, ⁷⁵Br, ⁷⁶Bror ⁷⁷Br will generally be most useful.

It is understood that a “radio-labeled” or “labeled compound” is acompound of Formula (Ia) that has incorporated at least oneradionuclide; in some embodiments the radionuclide is selected from thegroup consisting of ³H, ¹⁴C, ¹²⁵I, ³⁵S and ⁸²Br. Certainisotopically-labeled compounds of the present invention are useful incompound and/or substrate tissue distribution assays. In someembodiments the radionuclide ³H and/or ¹⁴C isotopes are useful in thesestudies. Further, substitution with heavier isotopes such as deuterium(i.e., ²H) may afford certain therapeutic advantages resulting fromgreater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the present inventioncan generally be prepared by following procedures analogous to thosedisclosed in the Schemes supra and Examples infra, by substituting anisotopically labeled reagent for a non-isotopically labeled reagent.Other synthetic methods that are useful are discussed infra. Moreover,it should be understood that all of the atoms represented in thecompounds of the invention can be either the most commonly occurringisotope of such atoms or the more scarce radio-isotope ornonradio-active isotope.

Synthetic methods for incorporating radio-isotopes into organiccompounds are applicable to compounds of the invention and are wellknown in the art. These synthetic methods, for example, incorporatingactivity levels of tritium into target molecules, are as follows:

A. Catalytic Reduction with Tritium Gas—This procedure normally yieldshigh specific activity products and requires halogenated or unsaturatedprecursors.

B. Reduction with Sodium Borohydride [³H]— This procedure is ratherinexpensive and requires precursors containing reducible functionalgroups such as aldehydes, ketones, lactones, esters, and the like.

C. Reduction with Lithium Aluminum Hydride [³H]—This procedure offersproducts at almost theoretical specific activities. It also requiresprecursors containing reducible functional groups such as aldehydes,ketones, lactones, esters, and the like.

D. Tritium Gas Exposure Labeling—This procedure involves exposingprecursors containing exchangeable protons to tritium gas in thepresence of a suitable catalyst.

E. N-Methylation using Methyl Iodide [³H]— This procedure is usuallyemployed to prepare O-methyl or N-methyl (³H) products by treatingappropriate precursors with high specific activity methyl iodide (³H).This method in general allows for higher specific activity, such as forexample, about 70-90 Ci/mmol.

Synthetic methods for incorporating activity levels of ¹²⁵I into targetmolecules include:

A. Sandmeyer and like reactions—This procedure transforms an aryl orheteroaryl amine into a diazonium salt, such as a tetrafluoroboratesalt, and subsequently to ¹²⁵I labeled compound using Na¹²⁵I. Arepresented procedure was reported by Zhu, D.-G. and co-workers in J.Org. Chem. 2002, 67, 943-948.

B. Ortho ¹²⁵Iodination of phenols—This procedure allows for theincorporation of ¹²⁵I at the ortho position of a phenol as reported byCollier, T. L. and co-workers in J. Labeled Compd Radiopharm. 1999, 42,S264-S266.

C. Aryl and heteroaryl bromide exchange with ¹²⁵I—This method isgenerally a two step process. The first step is the conversion of thearyl or heteroaryl bromide to the corresponding tri-alkyltinintermediate using for example, a Pd catalyzed reaction [i.e. Pd(Ph₃P)₄]or through an aryl or heteroaryl lithium, in the presence of atri-alkyltinhalide or hexaalkylditin [e.g., (CH₃)₃SnSn(CH₃)₃]. Arepresented procedure was reported by Bas, M.-D. and co-workers in J.Labeled Compd Radiopharm. 2001, 44, S280-S282.

A radio-labeled 5-HT_(2A) receptor compound of Formula (Ia) can be usedin a screening assay to identify/evaluate compounds. In general terms, anewly synthesized or identified compound (i.e., test compound) can beevaluated for its ability to reduce binding of the “radio-labeledcompound of Formula (Ia)” to the 5-HT_(2A) receptor. Accordingly, theability of a test compound to compete with the “radio-labeled compoundof Formula (Ia)” for the binding to the 5-HT_(2A) receptor directlycorrelates to its binding affinity.

The labeled compounds of the present invention bind to the 5-HT_(2A)receptor. In one embodiment the labeled compound has an IC₅₀ less thanabout 500 μM, in another embodiment the labeled compound has an IC₅₀less than about 100 μM, in yet another embodiment the labeled compoundhas an IC₅₀ less than about 10 μM, in yet another embodiment the labeledcompound has an IC₅₀ less than about 1 μM, and in still yet anotherembodiment the labeled inhibitor has an IC₅₀ less than about 0.1 μM.

Other uses of the disclosed receptors and methods will become apparentto those in the art based upon, inter alia, a review of this disclosure.

As will be recognized, the steps of the methods of the present inventionneed not be performed any particular number of times or in anyparticular sequence. Additional objects, advantages, and novel featuresof this invention will become apparent to those skilled in the art uponexamination of the following examples thereof, which are intended to beillustrative and not intended to be limiting.

EXAMPLES Example 1: Syntheses of Compounds of the Present Invention

Illustrated syntheses for compounds of the present invention are shownin FIGS. 1 through 8 where the symbols have the same definitions as usedthroughout this disclosure.

The compounds of the invention and their synthesis are furtherillustrated by the following examples. The following examples areprovided to further define the invention without, however, limiting theinvention to the particulars of these examples. The compounds describedherein, supra and infra, are named according to CS Chem Draw UltraVersion 7.0.1 or AutoNom 2000. In certain instances common names areused and it is understood that these common names would be recognized bythose skilled in the art.

Chemistry: Proton nuclear magnetic resonance (¹H NMR) spectra wererecorded on a Varian Mercury Vx-400 equipped with a 4 nucleus autoswitchable probe and z-gradient or a Bruker Avance-400 or 500 MHzequipped with a QNP (Quad Nucleus Probe) or a BBI (Broad Band Inverse)and z-gradient. Chemical shifts are given in parts per million (ppm)with the residual solvent signal used as reference. NMR abbreviationsare used as follows: s=singlet, d=doublet, dd=doublet of doublet,ddd=doublet of doublet of doublet, dt=doublet of triplet, t=triplet,q=quartet, m=multiplet, br=broad. Microwave irradiations were carriedout using the Emrys Synthesizer (Personal Chemistry). Thin-layerchromatography (TLC) was performed on silica gel 60 F₂₅₄ (Merck),preparatory thin-layer chromatography (prep TLC) was preformed on PK6Fsilica gel 60 A 1 mm plates (Whatman), and column chromatography wascarried out on a silica gel column using Kieselgel 60, 0.063-0.200 mm(Merck). Evaporation was done under reduced pressure on a Buchi rotaryevaporator. Celite 545® was used during palladium filtrations.

LCMS specs: 1) PC: HPLC-pumps: LC-10AD VP, Shimadzu Inc.; HPLC systemcontroller: SCL-10A VP, Shimadzu Inc; UV-Detector: SPD-10A VP, ShimadzuInc; Autosampler: CTC HTS, PAL, Leap Scientific; Mass spectrometer: API150EX with Turbo Ion Spray source, AB/MDS Sciex; Software: Analyst 1.2.2) Mac: HPLC-pumps: LC-8A VP, Shimadzu Inc; HPLC system controller:SCL-10A VP, Shimadzu Inc.

UV-Detector: SPD-10A VP, Shimadzu Inc; Autosampler: 215 Liquid Handler,Gilson Inc; Mass spectrometer: API 150EX with Turbo Ion Spray source,AB/MDS Sciex Software: Masschrom 1.5.2.

Example 1.1: Preparation ofN-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(1-methyl-piperidin-4-ylamino)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide

(Compound 45).

To a solution ofN-(4-(2-bromo-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl)-3-trifluoromethyl-benzamide(0.050 g, 99.5 μmol) in DMA (3 mL) were added1-methyl-piperidin-4-ylamine (17.0 mg, 149 μmol) andN,N-diisopropylethylamine (34.7 L, 199 μmol). The reaction mixture washeated at 150° C. for 30 minutes under microwave irradiation in aheavy-walled sealed tube, then purified by preparative HPLC. Thecorresponding fractions were collected and lyophilized to afford adouble TFA salt of the title compound in 40.1% yield as a white solid(hydroscopic). LCMS m/z (%)=536 (M+H, ³⁵Cl, 100), 538 (M+H, ³⁷Cl, 43).¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (s, 1H), 9.11-8.92 (m, 2H), 8.31-8.24(m, 2H), 8.01-7.95 (m, 2H), 7.80 (t, J=7.8 Hz, 1H), 7.73 (d, J=2.6 Hz,1H), 7.71 (s, 1H), 7.31 (d, J=9.1 Hz, 1H), 4.37-4.23 (m, 2H), 3.69 (s,3H), 3.42-3.05 (m, 4H), 2.93-2.80 (m, 2H), 2.78 (s, 3H), 2.18-2.07 (m,2H), 1.99-1.82 (m, 1H), 1.71-1.58 (m, 2H).

Example 1.2: Preparation ofN-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(tetrahydro-pyran-4-ylamino)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide

(Compound 61).

A mixture ofN-(4-(2-bromo-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl)-3-trifluoromethyl-benzamide(0.050 g, 99.5 μmol), tetrahydropyran-4-ylamine (15.1 mg, 149 mol) andN,N-diisopropylethylamine (34.7 L, 199 μmol) in DMA (3 mL) was heated at150° C. for 30 minutes under microwave irradiation in a heavy-walledsealed tube then purified by preparative HPLC. The correspondingfractions were collected and lyophilized to afford a TFA salt of thetitle compound in 66.7% yield as a white solid (hydroscopic). LCMS m/z(%)=523 (M+H, ³⁵Cl, 100), 525 (M+H, ³⁷Cl, 40). ¹H NMR (400 MHz, DMSO-d₆)δ 10.55 (s, 1H), 8.79-8.61 (m, 2H), 8.29-8.26 (m, 2H), 7.99-7.96 (m,2H), 7.80 (t, J=7.8 Hz, 1H), 7.71 (d, J=2.6 Hz, 1H), 7.69 (s, 1H), 7.31(d, J=9.1 Hz, 1H), 4.39-4.22 (m, 2H), 3.91-3.82 (m, 2H), 3.68 (s, 3H),3.41-3.29 (m, 1H), 3.22-3.05 (m, 4H), 1.85-1.73 (m, 2H), 1.51-1.32 (m,2H).

Example 1.3: Preparation ofN-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(1-methyl-piperidin-4-yloxy)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide(Compound 78)

To a solution ofN-(4-(2-bromo-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl)-3-trifluoromethyl-benzamide(0.100 g, 199 μmol) in DMA (3 mL) were added 1-methylpiperidin-4-ol(34.4 mg, 298 μmol) and N,N-diisopropylethylamine (69.5 μL, 398 μmol).The reaction mixture was heated at 150° C. for 30 minutes undermicrowave irradiation in a heavy-walled sealed tube then purified bypreparative HPLC. The corresponding fractions were collected andlyophilized to afford a TFA salt of the title compound in 35.5% yield asa white solid. LCMS m/z (%)=537 (M+H, ³⁵Cl, 100), 539 (M+H, ³⁷Cl, 40).

Example 1.4: Preparation of3-Methoxy-N-{3-(2-methyl-2H-pyrazol-3-yl)-4-[2-(3,3,3-trifluoro-propylamino)-ethoxy]-phenyl}-benzamide(Compound 72)

A mixture ofN-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide(14.5 mg, 81.9 μmol), 3-bromo-1,1,1-trifluoropropane (30 mg, 81.9 μmol)and triethylamine (34.2 μL, 246 μmol) in DMF was heated to 150° C. for 1hour under microwave irradiation in a heavy-walled sealed tube. Thecrude product was purified by HPLC. The proper fractions were collectedand lyophilized to afford the title compound as a brown solid in 2.3%yield. LCMS m/z (%)=463 (M+H, 100). ¹H NMR (400 MHz, MeOH-d₄) δ 2.6 (m,2H) 3.2 (dd, J=15.4, 7.8 Hz, 2H) 3.5 (m, 2H) 3.8 (s, 3H) 3.9 (s, 3H) 4.4(m, 2H) 6.4 (d, J=2.0 Hz, 1H) 7.2 (dd, J=8.6, 3.5 Hz, 1H) 7.3 (d, J=9.1Hz, 1H) 7.4 (t, J=8.1 Hz, 1H) 7.5 (m, 2H) 7.6 (d, J=2.0 Hz, 1H) 7.7 (d,J=2.5 Hz, 1H) 7.9 (dd, J=9.1, 2.5 Hz, 1H).

Example 1.5: Preparation ofN-[4-[2-(3-Cyano-propylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 80)

The title compound was prepared in a similar manner as described inExample 1.4 to give a white solid in 15.9% yield. LCMS m/z (%)=434 (M+H,100). ¹H NMR (400 MHz, MeOH-d₄) δ 1.8 (m, 2H) 2.4 (t, J=7.1 Hz, 2H) 2.9(m, 2H) 3.4 (m, 2H) 3.7 (s, 3H) 3.8 (s, 3H) 4.1 (m, 1H) 4.2 (m, 2H) 6.3(d, J=2.0 Hz, 1H) 7.0 (dd, J=8.1, 2.5 Hz, 1H) 7.1 (d, J=9.1 Hz, 1H) 7.3(t, J=8.1 Hz, 1H) 7.4 (m, 2H) 7.5 (d, J=2.0 Hz, 1H) 7.6 (d, J=2.5 Hz,1H) 7.7 (dd, J=9.1, 2.5 Hz, 1H).

Example 1.6: Preparation ofN-[4-[2-(Cyanomethyl-amino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 33)

The title compound was prepared in a similar manner as described inExample 1.4 to give a yellow oil in 16.1% yield. LCMS m/z=406 (M+H). ¹HNMR (400 MHz, MeOH-d₄) δ 3.5 (m, 2H) 3.8 (s, 3H) 3.9 (s, 3H) 4.0 (s, 2H)4.3 (m, 2H) 6.4 (d, J=2.0 Hz, 1H) 7.2 (dd, J=7.8, 3.3 Hz, 1H) 7.2 (d,J=9.1 Hz, 1H) 7.4 (t, J=7.8 Hz, 1H) 7.5 (m, 2H) 7.6 (d, J=2.0 Hz, 1H)7.7 (d, J=2.5 Hz, 1H) 7.9 (dd, J=8.8, 2.8 Hz, 1H).

Example 1.7: Preparation ofN-[4-[2-(2-Cyano-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 70)

The title compound was prepared in a similar manner as described inExample 1.4 to give a yellow oil in 4.72% yield. LCMS m/z (%)=420 (M+H,100).

Example 1.8: Preparation ofN-[4-[2-(2-Methanesulfonyl-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 4)

A mixture of 2-(methylsulfonyl)ethyl methanesulfonate (16.6 mg, 81.9μmol) andN-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide(30 mg, 81.9 μmol) in DMF was heated to 150° C. for 1 hour undermicrowave irradiation in a heavy-walled sealed tube. The crude productwas purified by HPLC. The proper fractions were collected andlyophilized to afford the title compound as a yellow solid in 18.5%yield. LCMS m/z (%)=473 (M+H, 100).

Example 1.9: Preparation ofN-[4-[2-(2,2-Difluoro-propylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 10)

The title compound was prepared in a similar manner as described inExample 1.8 to give a yellow oil in 5.63% yield. LCMS m/z (%)=445 (M+H,100).

Example 1.10: Preparation ofN-[4-(2-Acetimidoylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 21)

A mixture ofN-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide(30 mg, 81.9 μmol), ethyl acetimidate hydrochloride (12.1 mg, 98.2 μmol)and triethylamine (22.8 μL, 164 μmol) in dichloromethane was stirred atroom temperature overnight. The mixture was concentrated and the crudeproduct was purified by HPLC. The proper fractions were collected andlyophilized to afford the title compound as a white solid in 7.01%yield. LCMS m/z (%)=408 (M+H, 100). ¹H NMR (400 MHz, MeOH-d₄) δ 2.2 (s,2H) 2.7 (s, 3H) 3.0 (s, 1H) 3.6 (t, J=5.1 Hz, 2H) 3.7 (s, 3H) 3.9 (s,3H) 4.2 (t, J=5.1 Hz, 2H) 6.3 (d, J=2.0 Hz, 1H) 7.2 (dd, J=7.3, 2.8 Hz,1H) 7.2 (d, J=8.6 Hz, 1H) 7.4 (t, J=7.8 Hz, 1H) 7.5 (m, 2H) 7.6 (d,J=2.0 Hz, 1H) 7.7 (d, J=3.0 Hz, 1H) 7.8 (dd, J=9.1, 2.5 Hz, 1H).

Example 1.11: Preparation ofN-[4-(2-Guanidino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 44)

A mixture ofN-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide(30 mg, 81.87 μmol), 1,3-di-boc-2-(trifluoromethylsulfonyl)guanidine(38.45 mg, 98.25 μmol) and triethylamine (22.82 μL, 163.7 μmol) in DCMwas stirred at room temperature for 5 hours. Then to the mixture wasadded TFA (6.308 μL, 81.87 μmol) and the mixture was stirred overnight.The crude product was purified by column chromatography to afford thetitle compound as brown oil in 49.43% yield. LCMS m/z (%)=409 (M+H,100). ¹H NMR (400 MHz, MeOH-d₄) δ 3.5 (t, J=5.1 Hz, 2H) 3.7 (s, 3H) 3.9(s, 3H) 4.1 (t, J=5.1 Hz, 2H) 6.3 (d, J=2.0 Hz, 1H) 7.1 (d, J=5.6 Hz,1H) 7.2 (d, J=9.1 Hz, 1H) 7.4 (t, J=7.8 Hz, 1H) 7.5 (m, 2H) 7.5 (d,J=2.0 Hz, 1H) 7.6 (d, J=3.0 Hz, 1H) 7.8 (dd, J=8.8, 2.8 Hz, 1H).

Example 1.12: Preparation ofN-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(3,3,3-trifluoro-propylamino)-ethoxy]-phenyl}-2-fluoro-4-methoxy-benzamide(Compound 56) Step A: Preparation ofN-(4-(2-Aminoethoxy)-3-(4-chloro-1-methyl-1H-pyrazol-5-yl)phenyl)-2-fluoro-4-methoxybenzamide

A mixture of 2-fluoro-4-methoxybenzoic acid (92.8 mg, 545 μmol),tert-butyl2-(4-amino-2-(4-chloro-1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate(200 mg, 545 μmol), HATU (207 mg, 545 μmol) and triethylamine (76.0 μL,545 μmol) in dichloromethane was stirred at room temperature overnight.The reaction was diluted with dichloromethane and washed with water. Theorganic layer was separated, dried over anhydrous Na₂SO₄, filtered andconcentrated. To the crude product was added 2M HCl (5 eq.). The mixturewas stirred at room temperature overnight. The mixture was concentratedand the title compound was obtained as a yellow oil. LCMS m/z (%)=419(M+H, ³⁵Cl, 100), 421 (M+H, ³⁷Cl, 40).

Step B: Preparation ofN-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(3,3,3-trifluoro-propylamino)-ethoxy]-phenyl}-2-fluoro-4-methoxy-benzamide(Compound 56)

The title compound was prepared in a similar manner as described inExample 1.4 to give a yellow solid in 2.85% yield. LCMS m/z (%)=515(M+H, ³⁵Cl, 100), 517 (M+H, ³⁷Cl, 31).

Example 1.13: Preparation of 5-Methyl-isoxazole-3-carboxylic acid{3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(3,3,3-trifluoro-propylamino)-ethoxy]-phenyl}-amide(Compound 1)

Step A: Preparation ofN-(4-(2-Aminoethoxy)-3-(4-chloro-1-methyl-1H-pyrazol-5-yl)phenyl)-5-methylisoxazole-3-carboxamide.

The title compound was prepared in a similar manner as described inExample 1.12, Step A. LCMS m/z (%)=376 (M+H, ³⁵Cl, 100), 378 (M+H, ³⁷Cl,28).

Step B: Preparation of 5-Methyl-isoxazole-3-carboxylic acid{3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(3,3,3-trifluoro-propylamino)-ethoxy]-phenyl}-amide(Compound 1)

The title compound was prepared in a similar manner as described inExample 1.4 to give a brown oil in 2.79% yield. LCMS m/z=472 (M+H).

Example 1.14: Preparation of 5-Methyl-isoxazole-3-carboxylic acid{3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(2-methanesulfonyl-ethylamino)-ethoxy]-phenyl}-amide(Compound 8)

The title compound was prepared in a similar manner as described inExample 1.8 to give a brown oil in 1.3% yield. LCMS m/z (%)=482 (M+H,100).

Example 1.15: Preparation of3-Fluoro-N-{3-(2-methyl-2H-pyrazol-3-yl)-4-[2-(3,3,3-trifluoro-propylamino)-ethoxy]-phenyl}-benzamide(Compound 77)

The title compound was prepared in a similar manner as described inExample 1.4 to give a brown oil in 5.2% yield. LCMS m/z (%)=451 (M+H,100). ¹H NMR (400 MHz, MeOH-d₄) δ 2.6 (m, 2H) 3.2 (m, 2H) 3.5 (m, 2H)3.8 (s, 3H) 4.4 (m, 2H) 6.4 (d, J=2.0 Hz, 1H) 7.3 (d, J=9.1 Hz, 1H) 7.4(m, 1H) 7.6 (m, 2H) 7.7 (m, 2H) 7.8 (d, J=8.6 Hz, 1H) 7.9 (dd, J=8.8,2.8 Hz, 1H).

Example 1.16: Preparation ofN-[4-[2-(2-Cyano-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide(Compound 16)

The title compound was prepared in a similar manner as described inExample 1.4 to give a yellow oil in 2.85% yield. LCMS m/z (%)=408 (M+H,100). ¹H NMR (400 MHz, MeOH-d₄) δ 2.8 (t, J=6.8 Hz, 2H) 3.2 (t, J=7.1Hz, 2H) 3.5 (m, 2H) 3.8 (s, 3H) 4.4 (m, 2H) 6.4 (d, J=2.0 Hz, 1H) 7.3(d, J=8.6 Hz, 1H) 7.4 (m, 1H) 7.6 (m, 1H) 7.6 (t, J=2.3 Hz, 1H) 7.7 (m,2H) 7.8 (d, J=8.1 Hz, 1H) 7.9 (dd, J=8.6, 2.5 Hz, 1H).

Example 1.17: Preparation of3-Fluoro-N-[4-[2-(2-methanesulfonyl-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 28)

The title compound was prepared in a similar manner as described inExample 1.8 to give a brown oil in 9.4% yield. LCMS m/z (%)=461 (M+H,100).

Example 1.18: Preparation of2,4-Difluoro-N-{3-(2-methyl-2H-pyrazol-3-yl)-4-[2-(tetrahydro-pyran-4-ylamino)-ethoxy]-phenyl}-benzamide(Compound 19)

To a solution ofN-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2,4-difluoro-benzamide(0.050 g, 0.12 mmol) in N,N-dimethylacetamide (2.0 mL) was addedN,N-diisopropylethylamine (0.040 mL, 0.23 mmol) and4-aminotetrahydropyran (0.032 mL, 0.32 mmol) in a heavy-walled sealedtube. The solution was heated under microwave irradiation at 120° C. for1 h. The solution was concentrated and purified by RP-HPLC.Lyophilization afforded a TFA salt as a brown solid (0.039 g, 59%). LCMSm/z (%)=457 (M+H, 100). ¹H NMR (400 MHz, DMSO-d₆) δ 10.45 (s, 1H), 7.81(dd, J=2.6, 9.0 Hz, 1H), 7.79-7.72 (m, 1H), 7.66 (d, J=2.6 Hz, 1H), 7.52(d, J=1.8 Hz, 1H), 7.48-7.40 (m, 1H), 7.28-7.20 (m, 2H), 6.34 (d, J=1.8Hz, 1H), 4.28-4.23 (m, 2H), 3.84 (dd, J=4.0, 11.4 Hz, 2H), 3.69 (s, 3H),3.40-3.32 (m, 2H), 3.32-3.14 (m, 2H), 3.14-3.03 (m, 1H), 1.85 (m, 2H),1.48-1.36 (m, 2H).

Example 1.19: Preparation ofN-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(piperidin-4-ylamino)-ethoxy]-phenyl}-3-fluoro-benzamide(Compound 22)

A solution of4-{2-[2-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-fluoro-benzoylamino)-phenoxy]-ethylamino}-piperidine-1-carboxylicacid tert-butyl ester (0.035 g, 0.061 mmol) in 4 M HCl in dioxane (2.2mL) was shaken on a rotary stirrer for 3 hours. The reaction wasconcentrated and purified by RP-HPLC. Lyophilization afforded a TFA saltas a pale solid (0.021 g, 48%). LCMS m/z (%)=472 (M+H, ³⁵Cl, 100), 474(M+H, ³⁷Cl, 40). ¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H), 7.96 (dd,J=2.6, 9.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.77 (m, 1H), 7.73 (d, J=2.6Hz, 1H), 7.68 (s, 1H), 7.64-7.57 (m, 1H) 7.47 (dt, J=2.6, 8.8 Hz, 1H),7.30 (d, J=9.1 Hz, 1H), 4.37-4.22 (m, 2H), 3.69 (s, 3H), 3.42-3.28 (m,4H), 3.22-3.10 (m, 1H), 2.86-2.70 (m, 2H), 2.05 (d, J=12.1 Hz, 2H),1.65-1.50 (m, 2H).

Example 1.20: Preparation of4-{2-[2-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethyl-benzoylamino)-phenoxy]-ethylamino}-piperidine-1-carboxylicacid tert-butyl ester (Compound 23)

The title compound was prepared in a similar manner as described inExample 1.18 to afford a yellow solid, 59% yield. LCMS m/z (%)=622 (M+H,³⁵Cl, 100), 624 (M+H, ³⁷Cl, 40). ¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (s,1H), 8.30-8.24 (m, 2H), 7.97 (d, J=7.8 Hz, 1H), 7.90 (dd, J=2.6, 9.0 Hz,1H), 7.82-7.76 (m, 1H), 7.70 (d, J=2.6 Hz, 1H), 7.63 (s, 1H), 7.25 (d,J=9.1 Hz, 1H), 4.11-4.00 (m, 2H), 3.81-3.73 (m, 2H), 3.68 (s, 3H),2.86-2.70 (m, 4H), 1.72-1.66 (m, 2H), 1.57-1.48 (m, 1H), 1.39 (s, 9H),1.06-0.96 (m, 2H).

Example 1.21: Preparation of4-{2-[2-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-methoxy-benzoylamino)-phenoxy]-ethylamino}-piperidine-1-carboxylicacid tert-butyl ester (Compound 24)

The title compound was prepared in a similar manner as described inExample 1.18 to afford a pale solid as a TFA salt, 37% yield. LCMS m/z(%)=584 (M+H, ³⁵Cl, 100), 586 (M+H, ³⁷Cl, 26). ¹H NMR (400 MHz, DMSO-d₆)δ 10.31 (s, 1H), 7.98 (dd, J=2.4, 9.0 Hz, 1H), 7.72 (d, J=2.6 Hz, 1H),7.69 (s, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.49-7.43 (m, 2H), 7.28 (d, J=9.1Hz, 1H), 7.17 (dd, J=2.7, 8.9 Hz, 1H), 4.35-4.20 (m, 2H), 4.00-3.90 (m,2H), 3.85 (s, 3H), 3.68 (s, 3H), 3.40-3.30 (m, 2H), 3.15-3.03 (m, 1H),1.92-1.81 (m, 2H), 1.41 (s, 9H), 1.29-1.20 (m, 4H).

Example 1.22: Preparation of2,4-Difluoro-N-[4-[2-(1-methyl-piperidin-4-ylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 27)

The title compound was prepared in a similar manner as described inExample 1.18 to afford a pale solid as a TFA salt, 36% yield. LCMS m/z(%)=470 (M+H, 100). ¹H NMR (400 MHz, DMSO-d₆) δ 10.44 (s, 1H), 7.80 (dd,J=2.6, 9.0 Hz, 1H), 7.79-7.71 (m, 1H), 7.66 (d, J=2.6 Hz, 1H), 7.53 (d,J=6.2 Hz, 1H), 7.58-7.40 (m, 2H), 7.29-7.20 (m, 2H), 6.35 (d, J=1.8 Hz,1H), 4.28-4.22 (m, 2H), 3.70 (s, 3H), 3.50-2.74 (m, 9H), 2.14-2.06 (m,2H), 1.96-1.84 (m, 1H), 1.70-1.66 (m, 2H).

Example 1.23: Preparation ofN-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(piperidin-4-ylamino)-ethoxy]-phenyl}-3-methoxy-benzamide(Compound 32)

The title compound was prepared in a similar manner as described inExample 1.18 to afford a white solid as a TFA salt, 99% yield. LCMS m/z(%)=484 (M+H, ³⁵Cl, 100), 486 (M+H, ³⁷Cl, 43). ¹H NMR (400 MHz, DMSO-d₆)δ 10.30 (s, 1H), 7.96 (dd, J=2.6, 9.0 Hz, 1H), 7.74 (d, J=2.6 Hz, 1H),7.68 (s, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.49-7.47 (m, 1H), 7.45 (d, J=7.8Hz, 1H), 7.29 (d, J=9.1 Hz, 1H), 7.27 (dd, J=1.9, 8.1 Hz, 1H), 4.36-4.23(m, 2H), 3.84 (s, 3H), 3.70 (s, 3H), 3.38-3.28 (m, 4H), 3.22-3.11 (m,1H), 2.86-2.70 (m, 2H), 2.04 (d, J=12.3 Hz, 2H), 1.65-1.50 (m, 2H).

Example 1.24: Preparation ofN-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(1-methyl-piperidin-4-ylamino)-ethoxy]-phenyl}-3-fluoro-benzamide(Compound 34)

The title compound was prepared in a similar manner as described inExample 1.18 to afford a pale solid as a TFA salt, 28% yield. LCMS m/z(%)=486 (M+H, ³⁵Cl, 100), 488 (M+H, ³⁷Cl, 38). ¹H NMR (400 MHz, DMSO-d₆)δ 10.40 (s, 1H), 7.96 (dd, J=2.6, 9.0 Hz, 2H), 7.82 (d, J=7.9 Hz, 1H),7.80-7.75 (m, 1H), 7.74 (d, J=2.6 Hz, 1H), 7.65-7.57 (m, 1H), 7.47 (dt,J=2.7, 8.4 Hz, 1H), 7.30 (d, J=9.1 Hz, 1H), 4.36-4.22 (m, 2H), 3.69 (s,3H), 3.54-3.42 (m, 3H), 3.21-3.08 (m, 1H), 2.91-2.73 (m, 4H), 2.11 (d,J=12.7 Hz, 2H), 2.00-1.82 (m, 2H), 1.73-1.56 (m, 2H).

Example 1.25: Preparation of4-{2-[2-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-trifluoromethyl-benzoylamino)-phenoxy]-ethylamino}-piperidine-1-carboxylicacid ethyl ester (Compound 39)

The title compound was prepared in a similar manner as described inExample 1.18 to afford a yellow oil, 70% yield. LCMS m/z (%)=594 (M+H,³⁵Cl, 100), 596 (M+H, ³⁷Cl, 45). ¹H NMR (400 MHz, DMSO-d₆) δ 10.49 (s,1H), 8.29 (bs, 1H), 8.26 (d, J=8.0 Hz, 1H), 7.97 (d, J=7.9 Hz, 1H), 7.90(dd, J=2.6, 9.0 Hz, 1H), 7.79 (t, J=6.2 Hz, 1H), 7.69 (d, J=2.7 Hz, 1H),7.63 (s, 1H), 7.25 (d, J=9.1 Hz, 1H), 4.09 (q, J=5.3 Hz, 2H), 4.02 (q,J=7.1 Hz, 2H), 3.84-3.76 (m, 2H), 3.67 (s, 3H), 2.78-2.76 (m, 4H),1.74-1.50 (m, 3H), 1.17 (t, J=7.1 Hz, 3H), 1.08-0.98 (m, 2H).

Example 1.26: Preparation ofN-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(1-methyl-piperidin-4-ylamino)-ethoxy]-phenyl}-3-methoxy-benzamide(Compound 41)

The title compound was prepared in a similar manner as described inExample 1.18 to afford a tan solid as a TFA salt, 27% yield. LCMS m/z(%)=498 (M+H, ³⁵Cl, 100), 500 (M+H, ³⁷Cl, 51). ¹H NMR (400 MHz, DMSO-d₆)δ 10.31 (s, 1H), 7.97 (dd, J=2.7, 9.0 Hz, 1H), 7.73 (d, J=2.6 Hz, 1H),7.71 (s, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.49-7.47 (m, 2H), 7.29 (d, J=9.2Hz, 1H), 7.17 (dd, J=2.6, 8.2 Hz, 1H), 4.34-4.20 (m, 2H), 3.83 (s, 3H),3.68 (s, 3H), 3.22-3.10 (m, 1H), 2.90-2.73 (m, 4H), 2.55-2.45 (m, 3H),2.15-2.08 (m, 2H), 2.00-1.75 (m, 2H), 1.71-1.50 (m, 2H).

Example 1.27: Preparation ofN-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-((R)-6-oxo-piperidin-3-ylamino)-ethoxy]-phenyl}-3-methoxy-benzamide(Compound 49)

The title compound was prepared in a similar manner as described inExample 1.18 to afford a pale solid as a TFA salt, 8% yield. LCMS m/z(%)=498 (M+H, ³⁵Cl, 100), 500 (M+H, ³⁷Cl, 40). ¹H NMR (400 MHz, DMSO-d₆)δ 10.31 (s, 1H), 7.96 (dd, J=2.7, 9.1 Hz, 1H), 7.78-7.69 (m, 1H),7.68-7.64 (m, 1H), 7.56-7.51 (m, 1H), 7.50-7.46 (m, 1H), 7.44 (dd,J=2.3, 7.9 Hz, 1H), 7.28 (d, J=9.1 Hz, 1H), 7.19-7.14 (m, 1H), 4.36-4.24(m, 1H), 4.12-4.02 (m, 1H), 3.82 (s, 3H), 3.78-3.48 (m, 2H), 3.66 (s,3H), 3.20-3.10 (m, 1H), 2.96-2.80 (m, 2H), 2.11-2.10 (m, 1H), 1.30-1.18(m, 3H).

Example 1.28: Preparation ofN-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(tetrahydro-pyran-4-ylamino)-ethoxy]-phenyl}-3-fluoro-benzamide(Compound 51)

The title compound was prepared in a similar manner as described inExample 1.18 to afford a pale solid as a TFA salt, 69% yield. LCMS=473(M+H, ³⁵Cl, 100), 475 (M+H, ³⁷Cl, 19). ¹H NMR (400 MHz, DMSO-d₆) δ 10.40(s, 1H), 7.97 (dd, J=2.6, 9.0 Hz, 1H), 7.82 (d, J=7.8 Hz, 1H), 7.77 (dt,J=2.2, 9.9 Hz, 1H), 7.72 (d, J=2.6 Hz, 1H), 7.70 (s, 1H), 7.64-7.57 (m,1H), 7.46 (dt, J=2.7, 8.8 Hz, 1H), 7.30 (d, J=9.1 Hz, 1H), 4.36-4.23 (m,2H), 3.86 (dd, J=4.0, 11.4 Hz, 2H), 3.68 (s, 3H), 3.40-3.30 (m, 1H),3.23-3.05 (m, 4H), 1.79 (d, J=9.6 Hz, 2H), 1.50-1.35 (m, 2H).

Example 1.29: Preparation ofN-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(tetrahydro-pyran-4-ylamino)-ethoxy]-phenyl}-3-methoxy-benzamide(Compound 53)

The title compound was prepared in a similar manner as described inExample 1.18 to afford a pale solid as a TFA salt, 32% yield. LCMS m/z(%)=485 (M+H, ³⁵Cl, 100), 487 (M+H, ³⁷Cl, 36). ¹H NMR (400 MHz, DMSO-d₆)δ 10.31 (s, 1H), 7.97 (dd, J=2.7, 9.1 Hz, 1H), 7.73 (d, J=2.6 Hz, 1H),7.69 (s, 1H), 7.54 (d, J=7.8 Hz, 1H), 7.49-7.46 (m, 1H), 7.43 (d, J=7.8Hz, 1H), 7.28 (d, J=9.1 Hz, 1H), 7.17 (dd, J=2.6, 8.1 Hz, 1H), 4.35-4.22(m, 2H), 3.87 (dd, J=4.0, 11.6 Hz, 1H), 3.84 (s, 3H), 3.68 (s, 3H),3.40-3.14 (m, 2H), 3.25-3.14 (m, 4H), 1.79 (m, 2H), 1.48-1.35 (m, 2H).

Example 1.30: Preparation ofN-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(piperidin-4-ylamino)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide(Compound 60)

The title compound was prepared in a similar manner as described inExample 1.19 to afford a tan solid as an HCl salt, 99% yield. LCMS m/z(%)=522 (M+H, ³⁵Cl, 100), 524 (M+H, ³⁷Cl, 42). ¹H NMR (400 MHz, DMSO-d₆)δ 10.60 (s, 1H), 8.34-8.26 (m, 2H), 8.10-7.94 (m, 2H), 7.80 (t, J=7.8Hz, 1H), 7.75 (d, J=2.6 Hz, 1H), 7.68 (s, 1H), 7.32 (d, J=9.1 Hz, 1H),4.44-4.30 (m, 2H), 3.69 (s, 3H) 3.74-3.64 (m, 2H), 3.37-3.27 (m, 2H),3.21-3.10 (m, 1H), 2.86-2.70 (m, 2H), 2.09 (d, J=12.1 Hz, 2H), 1.83-1.70(m, 2H).

Example 1.31: Preparation of4-{2-[2-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(3-fluoro-benzoylamino)-phenoxy]-ethylamino}-piperidine-1-carboxylicacid tert-butyl ester (Compound 64)

The title compound was prepared in a similar manner as described inExample 1.18 to afford a pale solid as a TFA salt, 46% yield. LCMS m/z(%)=572 (M+H, ³⁵Cl, 100), 574 (M+H, ³⁷Cl, 40). ¹H NMR (400 MHz, DMSO-d₆)δ 10.40 (s, 1H), 7.97 (dd, J=2.6, 9.1 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H),7.79-7.74 (m, 1H), 7.72 (d, J=2.6 Hz, 1H), 7.69 (s, 1H), 7.64-7.57 (m,1H), 7.47 (dt, J=2.6, 8.8 Hz, 1H), 7.29 (d, J=9.2 Hz, 1H), 4.34 (m, 2H),4.02-3.87 (m, 2H), 3.68 (s, 3H), 3.41-3.31 (m, 2H), 3.13-3.02 (m, 1H),1.91-1.80 (m, 2H), 1.40 (s, 9H), 1.30-1.29 (m, 4H).

Example 1.32: Preparation ofN-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-hydroxy-ethoxy)-phenyl]-3-methoxy-benzamide(Compound 68)

The title compound was prepared in a similar manner as described inExample 1.18 to afford a pale solid, 14% yield. LCMS m/z (%)=402 (M+H,³⁵Cl, 100), 404 (M+H, ³⁷Cl, 33). ¹H NMR (400 MHz, DMSO-d₆) δ 10.24 (s,1H), 7.88 (dd, J=2.6, 9.0 Hz, 1H), 7.71 (d, J=2.6 Hz, 1H), 7.62 (s, 1H),7.53 (d, J=7.8 Hz, 1H), 7.48 (m, 1H), 7.44 (t, J=8.0 Hz, 1H), 7.23 (d,J=9.1 Hz, 1H), 7.16 (dd, J=2.4, 8.0 Hz, 1H), 4.11-4.00 (m, 2H), 3.83 (s,3H), 3.68 (s, 3H), 3.70-3.62 (m, 2H).

Example 1.33: Preparation ofN-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(1-methyl-piperidin-4-yloxy)-ethoxy]-phenyl}-3-methoxy-benzamide(Compound 71)

The title compound was prepared in a similar manner as described inExample 1.18 to afford an orange solid, 41% yield. LCMS m/z (%)=499(M+H, ³⁵Cl, 100), 451 (M+H, ³⁷Cl, 40). ¹H NMR (400 MHz, DMSO-d₆) δ 10.28(s, 1H), 7.96 (dd, J=2.5, 9.0 Hz, 1H), 7.72 (m, 1H), 7.65 (d, J=8.2 Hz,1H), 7.55 (d, J=7.8 Hz, 1H), 7.50-7.48 (m, 1H), 7.45 (t, J=7.9 Hz, 1H),7.31 (dd, J=2.5, 9.1 Hz, 1H), 7.17 (dd, J=2.5, 8.2 Hz, 1H), 5.16-4.92(m, 1H), 4.55-4.46 (m, 2H), 3.83 (s, 3H), 3.86-3.64 (m, 2H), 3.66 (s,3H), 3.50-3.12 (m, 4H), 2.95 (m, 3H), 1.98-1.49 (m, 4H).

Example 1.34: Preparation ofN-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(1-methyl-piperidin-4-yloxy)-ethoxy]-phenyl}-3-fluoro-benzamide(Compound 73)

The title compound was prepared in a similar manner as described inExample 1.18 to afford a pale solid as a TFA salt, 87% yield. LCMS m/z(%)=487 (M+H, ³⁵Cl, 100), 489 (M+H, ³⁷Cl, 47). ¹H NMR (400 MHz, DMSO-d₆)δ 10.41 (s, 1H), 7.96 (dd, J=2.6, 9.0 Hz, 1H), 7.82 (d, J=7.9 Hz, 1H),7.78 (m, 1H), 7.72 (m, 1H), 7.65 (d, J=8.2 Hz, 1H), 7.63-7.57 (m, 1H),7.46 (dt, J=2.5, 8.7 Hz, 1H), 7.32 (dd, J=2.5, 9.1 Hz, 1H), 5.20-4.92(m, 1H), 4.56-4.45 (m, 2H), 3.86-3.68 (m, 2H), 3.66 (s, 3H), 3.48-3.13(m, 4H), 3.01-2.90 (m, 3H), 1.98-1.50 (m, 4H).

Example 1.35: Preparation ofN-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-hydroxy-ethoxy)-phenyl]-3-fluoro-benzamide(Compound 76)

The title compound was prepared in a similar manner as described inExample 1.18 to afford a pale solid as a TFA salt. LCMS m/z (%)=390(M+H, ³⁵Cl, 100), 392 (M+H, ³⁷Cl, 33). ¹H NMR (400 MHz, DMSO-d₆) δ 10.32(s, 1H), 7.89 (dd, J=2.6, 9.0 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.79-7.74(m, 1H), 7.71 (d, J=2.6 Hz, 1H), 7.63 (s, 1H), 7.63-7.56 (m, 1H), 7.45(dt, J=2.5, 8.3 Hz, 1H), 7.24 (d, J=9.1 Hz, 1H), 4.12-4.00 (m, 2H),3.71-3.63 (m, 2H), 3.68 (s, 3H).

Example 1.36: Preparation ofN-[4-[2-(2-Hydroxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide(Compound 59)

A mixture ofN-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethyl-benzamide(0.500 g, 1.07 mmol), ethanolamine (0.0969 mL, 1.60 mmol) andN,N-diisopropylethylamine (0.372 mL, 2.14 mmol) in 3.0 mL of DMA washeated to 150° C. for 30 minutes under microwave irradiation in aheavy-walled sealed tube. The reaction mixture was diluted with DMSO andpurified by preparative HPLC. The proper fractions were collected andlyophilized to afford a TFA salt of the title compound as a semi-solidin 65% yield. LCMS m/z=449 (M+H). 1H NMR (400 MHz, DMSO-d₆) δ 10.56 (s,1H), 8.16 (d, J₁=8.08 Hz, 2H), 7.91 (d, J=8.08 Hz, 2H), 7.75 (s, 1H),7.48 (s, 1H), 7.23 (d, J=8.89 Hz, 1H), 6.32 (s, 1H), 5.24 (t, J=5.56 Hz,1H), 4.32 (t, J=5.80 Hz, 2H), 3.70 (s, 3H), 3.55 (q, J=10.61 Hz, 2H),3.30 (t, J=5.50 Hz, 2H), 2.85 (t, J=5.50 Hz, 2H).

Example 1.37:N-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(2-hydroxy-ethylamino)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide(Compound 3)

A mixture ofN-[4-(2-bromo-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide(0.400 g, 0.8 mmol), ethanolamine (0.07 mL, 1 mmol) andN,N-diisopropylethylamine (0.3 mL, 2 mmol) in 3.0 mL of DMA was heatedto 150° C. for 30 minutes under microwave irradiation in a heavy-walledsealed tube. The reaction mixture was diluted with DMSO and purified bypreparative HPLC. The proper fractions were collected and lyophilized toafford a TFA salt of the title compound as a semi-solid in 52% yield.LCMS m/z (%)=482 (M+H, ³⁵Cl, 100), 484 (M+H, ³⁷Cl, 40). ¹H NMR (400 MHz,DMSO-d₆) δ 10.61 (s, 1H), 8.27-8.32 (m, 2H), 7.94-8.00 (m, 1H), 7.92 (s,1H), 7.79 (t, J=7.71 Hz, 1H), 7.74 (d, J=2.78 Hz, 1H), 7.66 (s, 1H),7.30 (d, J=9.09 Hz, 1H), 5.24 (t, J=4.80 Hz, 1H), 4.27-4.41 (m, 2H),3.67 (m, 3H), 3.52-3.59 (m, 2H), 3.29 (t, J=5.56 Hz, 2H), 2.82-2.88 (m,2H).

Example 1.38:N-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-ethylamino-ethoxy)-phenyl]-3-trifluoromethyl-benzamide(Compound 12)

A mixture ofN-[4-(2-bromo-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide(0.0900 g, 0.179 mmol), ethylamine (0.0155 mL, 0.269 mmol),N,N-diisopropylethylamine (0.0624 mL, 0.358 mmol) in 2.0 mL of DMA washeated to 120° C. for 30 minutes under microwave irradiation in aheavy-walled sealed tube. The reaction mixture was diluted with DMSO andpurified by preparative HPLC. The proper fractions were collected andlyophilized to afford a TFA salt of the title compound as a semi-solidin 88% yield. LCMS m/z (%)=467 (M+H, ³⁵Cl, 100), 469 (M+H, ³⁷Cl, 40). ¹HNMR (400 MHz, DMSO-d₆) δ 10.56 (s, 1H), 8.23-8.36 (m, 2H), 7.90-8.05 (m,2H), 7.72-7.87 (m, 1H), 7.73 (d, J=2.78 Hz, 1H), 7.67 (s, 1H), 7.31 (d,J=9.09 Hz, 1H), 4.18-4.39 (m, 2H), 3.67 (s, 3H), 3.28 (t, J=5.81 Hz,2H), 2.75-2.91 (m, 2H), 1.05 (t, J=6.57 Hz, 3H).

Example 1.39: Preparation ofN-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(2-methoxy-ethylamino)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide(Compound 15)

A mixture ofN-[4-(2-bromo-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide(0.090 g, 0.179 mmol), 2-methoxyethylamine (0.0202 mL, 0.269 mmol) andN,N-diisopropylethylamine (0.0624 mL, 0.358 mmol) in 2.0 mL of DMA washeated to 120° C. for 30 minutes under microwave irradiation in aheavy-walled sealed tube. The reaction mixture was diluted with DMSO andpurified by preparative HPLC. The proper fractions were collected andlyophilized to afford a TFA salt of the title compound as a semi-solidin 91% yield. LCMS m/z (%)=498 (M+H, ³⁵Cl, 100), 500 (M+H, ³⁷Cl, 40). ¹HNMR (400 MHz, DMSO-d₆) δ 10.56 (s, 1H), 8.23-8.32 (m, 2H), 7.93-8.02 (m,2H), 7.80 (t, J=7.83 Hz, 1H), 7.72 (d, J=2.53 Hz, 1H), 7.67 (s, 1H),7.29 (d, J=9.09 Hz, 1H), 4.21-4.40 (m, 2H), 3.67 (s, 3H), 3.3-3.4 (m,4H), 3.29 (s, 3H), 2.96-3.01 (m, 2H), 1.18 (d, J=6.06 Hz, 1H).

Example 1.40: Preparation ofN-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(1,1-dimethyl-propylamino)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide(Compound 18)

A mixture ofN-[4-(2-bromo-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide(0.090 g, 0.179 mmol), tert-amylamine (0.0314 mL, 0.269 mmol) andN,N-diisopropylethylamine (0.0624 mL, 0.358 mmol) in 2.0 mL of DMA washeated to 120° C. for 30 minutes under microwave irradiation in aheavy-walled sealed tube. The reaction mixture was diluted with DMSO andpurified by preparative HPLC. The proper fractions were collected andlyophilized to afford a TFA salt of the title compound as a semi-solidin 27% yield. LCMS m/z (%)=509 (M+H, ³⁵Cl, 100), 511 (M+H, ³⁷Cl, 40). ¹HNMR (400 MHz, DMSO-d₆) δ 10.56 (s, 1H), 8.22-8.33 (m, 3H), 7.94-8.02 (m,2H), 7.80 (t, J=7.71 Hz, 1H), 7.73 (d, J=2.53 Hz, 1H), 7.30 (d, J=9.09Hz, 1H), 4.15-4.36 (m, 2H), 3.67-3.74 (m, 3H), 3.56-3.66 (m, 2H),3.21-3.31 (m, 2H), 1.52 (q, J=7.58 Hz, 2H), 1.14 (s, 6H), 0.80 (t,J=7.45 Hz, 3H).

Example 1.41: Preparation ofN-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-isobutylamino-ethoxy)-phenyl]-3-trifluoromethyl-benzamide(Compound 31)

A mixture ofN-[4-(2-bromo-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide(0.090 g, 0.179 mmol), iso-butylamine (0.0196 g, 0.269 mmol) andN,N-diisopropylethylamine (0.0624 mL, 0.358 mmol) in 2.0 mL of DMA washeated to 120° C. for 30 minutes under microwave irradiation in aheavy-walled sealed tube. The reaction mixture was diluted with DMSO andpurified by preparative HPLC. The proper fractions were collected andlyophilized to afford a TFA salt of the title compound as a semi-solidin 76% yield. LCMS m/z (%)=495 (M+H, ³⁵Cl, 100), 497 (M+H, ³⁷Cl, 40). ¹HNMR (400 MHz, DMSO-d₆) δ 10.56 (s, 1H), 8.40-8.45 (m, 1H), 8.23-8.32 (m,2H), 7.94-8.01 (m, 2H), 7.80 (t, J=7.71 Hz, 1H), 7.72 (d, J=2.53 Hz,1H), 7.66 (s, 1H), 7.29 (d, J=9.09 Hz, 1H), 4.24-4.39 (m, 2H), 3.68 (s,3H), 3.36 (s, 2H), 2.61 (d, J=3.28 Hz, 2H), 1.74-1.89 (m, 1H), 0.86 (dd,J=6.69, 1.89 Hz, 6H).

Example 1.42: Preparation ofN-[4-(2-Benzylamino-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide(Compound 36)

A mixture ofN-[4-(2-bromo-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide(0.090 g, 0.179 mmol), benzylamine (0.0293 mL, 0.269 mmol) andN,N-diisopropylethylamine (0.0624 mL, 0.358 mmol) in 2.0 mL of DMA washeated to 120° C. for 30 minutes under microwave irradiation in aheavy-walled sealed tube. The reaction mixture was diluted with DMSO andpurified by preparative HPLC. The proper fractions were collected andlyophilized to afford a TFA salt of the title compound as a semi-solidin 74% yield. LCMS m/z (%)=530 (M+H, ³⁵Cl, 100), 532 (M+H, ³⁷Cl, 40). ¹HNMR (400 MHz, DMSO-d₆) δ 10.57 (s, 1H), 8.98-9.05 (m, 1H), 8.22-8.33 (m,2H), 7.92-8.02 (m, 2H), 7.80 (t, J=7.83 Hz, 1H), 7.74 (d, J=2.78 Hz,1H), 7.63 (s, 1H), 7.40-7.48 (m, 3H), 7.33-7.40 (m, 2H), 7.31 (d, J=9.09Hz, 1H), 4.27-4.43 (m, 2H), 4.02 (dd, J=15.92 Hz, 2H), 3.69 (s, 3H),3.35-3.42 (m, 2H).

Example 1.43: Preparation ofN-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-cyclopropylamino-ethoxy)-phenyl]-3-trifluoromethyl-benzamide(Compound 47)

A mixture ofN-[4-(2-bromo-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide(0.090 g, 0.179 mmol), cyclopropylamine (0.0186 mL, 0.269 mmol) andN,N-diisopropylethylamine (0.0624 mL, 0.358 mmol) in 2.0 mL of DMA washeated to 120° C. for 30 minutes under microwave irradiation in aheavy-walled sealed tube. The reaction mixture was diluted with DMSO andpurified by preparative HPLC. The proper fractions were collected andlyophilized to afford a TFA salt of the title compound as a semi-solidin 84% yield. LCMS m/z (%)=480 (M+H, ³⁵Cl, 100), 482 (M+H, ³⁷Cl, 40). ¹HNMR (400 MHz, DMSO-d₆) δ 10.56 (s, 1H), 8.75-8.90 (m, 1H), 8.23-8.32 (m,2H), 7.92-8.02 (m, 2H), 7.80 (t, J=7.71 Hz, 1H), 7.73 (d, J=2.78 Hz,1H), 7.65 (s, 1H), 7.31 (d, J=9.09 Hz, 1H), 4.22-4.40 (m, 2H), 3.68 (s,4H), 3.34-3.45 (m, 2H), 0.56-0.78 (m, 4H).

Example 1.44: Preparation ofN-{3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(2-fluoro-ethylamino)-ethoxy]-phenyl}-3-trifluoromethyl-benzamide(Compound 58)

A mixture ofN-[4-(2-bromo-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide(0.090 g, 0.179 mmol), 2-fluoroethylamine hydrochloride (0.03 g, 0.269mmol) and N,N-diisopropylethylamine (0.0624 mL, 0.358 mmol) in 2.0 mL ofDMA was heated to 120° C. for 30 minutes under microwave irradiation ina heavy-walled sealed tube. The reaction mixture was diluted with DMSOand purified by preparative HPLC. The proper fractions were collectedand lyophilized to afford a TFA salt of the title compound as asemi-solid in 25% yield. LCMS m/z (%)=485 (M+H, ³⁵Cl, 100), 487 (M+H,³⁷Cl, 40). ¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (s, 1H), 8.21-8.33 (m, 2H),7.93-8.03 (m, 2H), 7.80 (t, J=7.71 Hz, 1H), 7.73 (d, J=2.53 Hz, 1H),7.66-7.69 (m, 1H), 7.31 (d, J=9.09 Hz, 1H), 4.62-4.72 (m, 1H), 4.56 (t,J=4.67 Hz, 1H), 4.24-4.41 (m, 2H), 3.67 (s, 3H), 3.34-3.43 (m, 2H),3.08-3.26 (m, 2H), 1.21-1.29 (m, 1H).

Example 1.45: Preparation ofN-[4-[2-(Carbamoylmethyl-amino)-ethoxy]-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide(Compound 29)

A mixture ofN-[4-(2-bromo-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide(0.0900 g, 0.179 mmol), glycinamide hydrochloride (0.0297 g, 0.269mmol), N,N-diisopropylethylamine (0.0624 mL, 0.358 mmol) in 2.0 mL ofDMA was heated to 120° C. for 30 minutes under microwave irradiation ina heavy-walled sealed tube. The reaction mixture was diluted with DMSOand purified by preparative HPLC. The proper fractions were collectedand lyophilized to afford a TFA salt of the title compound as asemi-solid in 65% yield. LCMS m/z (%)=496 (M+H, ³⁵Cl, 100), 498 (M+H,³⁷Cl, 40). ¹H NMR (400 MHz, DMSO-d₆) δ 10.55 (s, 1H), 8.23-8.32 (m, 2H),7.91-8.01 (m, 2H), 7.80 (t, J=7.83 Hz, 1H), 7.75 (t, 1H), 7.72 (d,J=2.53 Hz, 1H), 7.66 (s, 1H), 7.61 (s, 1H), 7.30 (d, J=9.09 Hz, 1H),4.21-4.37 (m, 2H), 3.63-3.70 (m, 5H), 1.20-1.29 (m, 2H).

Example 1.46: Preparation of2,4-Difluoro-N-[4-[2-(2-hydroxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 13)

A mixture ofN-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2,4-difluoro-benzamide(0.100 g, 0.2292 mmol), ethanolamine (0.0138 mL, 0.2292 mmol) andpotassium carbonate (0.06366 g, 0.4585 mmol) in 2.0 mL of DMA was heatedto 120° C. for 30 minutes under microwave irradiation in a heavy-walledsealed tube. The reaction mixture was diluted with DMSO and purified bypreparative HPLC. The proper fractions were collected and lyophilized toafford a TFA salt of the title compound in 47% yield. LCMS m/z=417(M+H). ¹H NMR (400 MHz, DMSO-d₆) δ 10.43 (s, 1H), 7.70-7.84 (m, 2H),7.66 (d, J=2.53 Hz, 1H), 7.48 (d, J=2.02 Hz, 1H), 7.40-7.47 (m, 1H),7.17-7.28 (m, 2H), 6.32 (d, J=1.77 Hz, 1H), 4.27 (t, J=5.18 Hz, 2H),3.68 (s, 5H), 3.50-3.56 (m, 2H), 3.26-3.36 (m, 2H), 2.85 (s, 2H).

Example 1.47: Preparation of3-Fluoro-N-[4-[2-(2-hydroxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 69)

A mixture ofN-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide(0.2770 g, 0.66227 mmol), and N,N-diisopropylethylamine (0.23071 mL,1.3245 mmol) in 1 mL of DMA was heated to 150° C. for 0.5 hours undermicrowave irradiation in a heavy-walled sealed tube. The reactionmixture was diluted with DMSO and purified by preparative HPLC. Theproper fractions were collected and lyophilized to afford a TFA salt ofthe title compound as a semi-solid in 37% yield. LCMS m/z=399 (M+H). ¹HNMR (400 MHz, DMSO-d₆) δ 10.36 (s, 1H), 7.88 (dd, J=8.97, 2.65 Hz, 1H),7.81 (d, J=7.83 Hz, 1H), 7.73-7.79 (m, 1H), 7.72 (d, J=2.53 Hz, 1H),7.56-7.64 (m, 1H), 7.49 (d, J=1.77 Hz, 1H), 7.43-7.50 (m, 1H), 7.23 (d,J=8.84 Hz, 1H), 6.23 (d, J=2.35, 1H) 4.28 (t, J=5.31 Hz, 2H), 3.69 (s,3H), 3.50-3.57 (m, 2H), 3.27-3.37 (m, 2H), 2.79-2.92 (m, 2H).

Example 1.48: Preparation ofN-[4-[2-(2-Hydroxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 43)

A mixture ofN-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(0.700 g, 1.627 mmol), ethanolamine (0.1476 mL, 2.440 mmol) andN,N-diisopropylethylamine (0.5682 mL, 3.254 mmol) in 10 mL of DMA washeated to 150° C. for 0.5 hours under microwave irradiation in aheavy-walled sealed tube. The reaction mixture was diluted with DMSO andpurified by preparative HPLC. The proper fractions were collected andlyophilized to afford a TFA salt of the title compound as a semi-solidin 43% yield. LCMS m/z=411 (M+H). ¹H NMR (400 MHz, DMSO-d₆) 2.83-2.89(m, 2H), 3.27-3.37 (m, 2H), 3.50-3.57 (m, 2H), 3.69 (s, 3H), 3.83 (s,3H), 4.28 (t, J=5.31 Hz, 2H), 6.32 (d, J=2.35 Hz, 1H) 7.15 (dd, J=7.47,1.89 Hz, 1H), 7.23 (d, J=8.84 Hz, 1H) 7.43-7.50 (m, 3H), 7.52 (d, J=7.77Hz, 1H), 7.72 (d, J=2.64 Hz, 1H), 7.88 (dd, J=8.97, 2.65 Hz, 1H), 10.36(s, 1H).

Example 1.49: Preparation of Cyclopropanecarboxylic acid{3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-[2-(2-hydroxy-ethylamino)-ethoxy]-phenyl}-amide(Compound 65)

A mixture of cyclopropanecarboxylic acid[4-(2-bromo-ethoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-amide(0.2500 g, 0.6271 mmol), ethanolamine (0.03785 mL, 0.6271 mmol) andN,N-diisopropylamine (0.2184 mL, 1.254 mmol) in 1 mL of DMA was heatedto 150° C. for 0.5 hours under microwave irradiation in a heavy-walledsealed tube. The reaction mixture was diluted with DMSO and purified bypreparative HPLC. The proper fractions were collected and lyophilized toafford a TFA salt of the title compound as a semi-solid in 75% yield.LCMS m/z=380 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ 10.29 (s, 1H), 7.73 (dd,J=8.97, 2.65 Hz, 1H), 7.64 (s, 1H), 7.54 (d, J=2.53 Hz, 1H), 7.20 (d,J=8.84 Hz, 1H), 5.27 (br. s., 1H), 4.16-4.36 (m, 2H), 3.63 (s, 2H),3.49-3.56 (m, 4H), 3.28-3.30 (m, 2H), 2.85 (d, J=1.01 Hz, 2H), 1.69-1.80(m, 1H), 0.79 (d, J=6.32 Hz, 4H).

Example 1.50: Preparation of3-Methoxy-N-[4-[2-(2-methoxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 38)

A mixture ofN-(4-(2-bromoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide(0.0660 g, 0.15338 mmol), N,N-diisopropylethylamine (0.080366 mL,0.46015 mmol) and 2-methoxyethanamine (0.020094 mL, 0.23007 mmol) in 1mL of DMA was heated to 160° C. for 0.5 hours under microwaveirradiation in a heavy-walled sealed tube. The reaction mixture wasdiluted with DMSO and purified by preparative HPLC. The proper fractionswere collected and lyophilized to afford a TFA salt of the titlecompound as a semi-solid in 92% yield. LCMS m/z=425 (M+H). ¹H NMR (400MHz, DMSO-d₆) δ 10.27 (s, 1H), 7.88 (dd, J=8.97, 2.65 Hz, 1H), 7.72 (d,J=2.78 Hz, 1H), 7.32-7.58 (m, 4H), 7.14-7.25 (m, 2H), 6.33 (d, J=1.77Hz, 1H), 4.27 (t, J=5.31 Hz, 5H), 3.84 (s, 3H), 3.69 (s, 3H), 3.42-3.48(m, 2H), 3.30-3.36 (m, 2H), 2.92-3.01 (m, 2H).

Example 1.51: Preparation ofN-[4-[2-(2-Ethoxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 55)

A mixture ofN-(4-(2-bromoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide(0.0644 g, 0.1497 mmol), N,N-diisopropylethylamine (0.07842 mL, 0.4490mmol), and 2-ethoxyethylamine (0.01334 g, 0.1497 mmol) in 1 mL of DMAwas heated to 160° C. for 0.5 hours under microwave irradiation in aheavy-walled sealed tube. The reaction mixture was diluted with DMSO andpurified by preparative HPLC. The proper fractions were collected andlyophilized to afford a TFA salt of the title compound as a semi-solidin 85% yield. LCMS m/z=439 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ 10.28 (s,1H), 7.88 (dd, J=8.97, 2.65 Hz, 1H), 7.73 (d, J=2.53 Hz, 1H), 7.40-7.60(m, 4H), 7.22 (d, J=9.09 Hz, 1H), 7.17 (dd, J=8.08, 2.53 Hz, 1H), 6.33(d, J=2.02 Hz, 1H), 4.28 (t, J=5.31 Hz, 2H), 3.84 (s, 3H), 3.69 (s, 3H),3.41-3.51 (m, 4H), 3.29-3.37 (m, 2H), 2.96 (br. s., 2H), 1.14 (t, J=6.95Hz, 3H).

Example 1.52: Preparation ofN-[4-[2-(2-Isopropoxy-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 63)

A mixture ofN-(4-(2-bromoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide(0.06650 g, 0.1545 mmol), 2-aminoethyl isopropyl ether (0.01594 g,0.1545 mmol) and N,N-diisopropylethylamine (0.08098 mL, 0.4636 mmol) in1 mL of DMA was heated to 160° C. for 0.5 hours under microwaveirradiation in a heavy-walled sealed tube. The reaction mixture wasdiluted with DMSO and purified by preparative HPLC. The proper fractionswere collected and lyophilized to afford a TFA salt of the titlecompound as a semi-solid in 69% yield. LCMS m/z=453 (M+H). ¹H NMR (400MHz, DMSO-d₆) δ 10.27 (s, 1H), 7.88 (dd, J=8.97, 2.65 Hz, 1H), 7.72 (d,J=2.78 Hz, 1H), 7.38-7.59 (m, 4H), 7.22 (d, J=9.09 Hz, 1H), 7.14-7.20(m, 1H), 6.32 (d, J=1.77 Hz, 1H), 4.24-4.32 (m, 2H), 3.84 (s, 3H), 3.69(s, 3H), 3.53-3.61 (m, 2H), 3.41-3.51 (m, 2H), 3.27-3.38 (m, 2H),2.91-2.99 (m, 2H), 1.11 (d, J=6.06 Hz, 6H).

Example 1.53: Preparation ofN-[4-(2-tert-Butylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 66)

A mixture ofN-(4-(2-bromoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide(0.0593 g, 0.1378 mmol), tert-butylamine (0.01461 mL, 0.1378 mmol) andN,N-diisopropylethylamine (0.07221 mL, 0.4134 mmol) in 1 mL of DMA washeated to 160° C. for 0.5 hours under microwave irradiation in aheavy-walled sealed tube. The reaction mixture was diluted with DMSO andpurified by preparative HPLC. The proper fractions were collected andlyophilized to afford a TFA salt of the title compound as a semi-solidin 89% yield. LCMS m/z=453 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ 10.26 (s,1H), 7.89 (dd, J=8.97, 2.65 Hz, 1H), 7.73 (d, J=2.53 Hz, 1H), 7.41-7.58(m, 4H), 7.23 (d, J=9.09 Hz, 1H), 7.17 (dd, J=8.08, 2.53 Hz, 1H), 6.37(d, J=1.77 Hz, 1H), 4.21 (t, J=5.05 Hz, 2H), 3.84 (s, 3H), 3.72 (s, 3H),3.25 (d, J=5.81 Hz, 2H), 1.21 (s, 9H).

Example 1.54: Preparation ofN-[4-(2-Isopropylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 74)

A mixture ofN-(4-(2-bromoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide(0.0557 g, 0.1294 mmol), isopropylamine (0.01109 mL, 0.1294 mmol) andN,N-diisopropylethylamine (0.06782 mL, 0.3883 mmol) in 1 mL of DMA washeated to 160° C. for 0.5 hours under microwave irradiation in aheavy-walled sealed tube. The reaction mixture was diluted with DMSO andpurified by preparative HPLC. The proper fractions were collected andlyophilized to afford a TFA salt of the title compound as a semi-solidin 84% yield. LCMS m/z=409 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ 10.27 (s,1H), 7.89 (dd, J=9.09, 2.53 Hz, 1H), 7.72 (d, J=2.53 Hz, 1H), 7.39-7.57(m, 4H), 7.23 (d, J=8.84 Hz, 1H), 7.17 (dd, J=8.34, 2.53 Hz, 1H), 6.34(d, J=1.77 Hz, 1H), 4.25 (t, J=5.18 Hz, 2H), 3.84 (s, 3H), 3.70 (s, 3H),3.26-3.36 (m, 2H), 3.09-3.20 (m, 1H), 1.12 (d, J=6.32 Hz, 6H).

Example 1.55: Preparation of3-Methoxy-N-[3-(2-methyl-2H-pyrazol-3-yl)-4-(2-propylamino-ethoxy)-phenyl]-benzamide(Compound 79)

A mixture ofN-(4-(2-bromoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide(0.0510 g, 0.1185 mmol), n-propylamine (0.009744 mL, 0.1185 mmol) andN,N-diisopropylethylamine (0.06210 mL, 0.3556 mmol) in 1 mL of DMA washeated to 160° C. for 0.5 hours under microwave irradiation in aheavy-walled sealed tube. The reaction mixture was diluted with DMSO andpurified by preparative HPLC. The proper fractions were collected andlyophilized to afford a TFA salt of the title compound as a semi-solidin 69% yield. LCMS m/z=409 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ 10.26 (s,2H), 7.89 (dd, J=9.09, 2.53 Hz, 1H), 7.72 (d, J=2.53 Hz, 1H), 7.41-7.57(m, 4H), 7.22 (d, J=9.09 Hz, 1H), 7.14-7.19 (m, 1H), 6.33 (d, J=2.02 Hz,1H), 4.26 (t, J=5.05 Hz, 2H), 3.84 (s, 3H), 3.70 (s, 3H), 3.24-3.36 (m,2H), 2.64-2.79 (m, 2H), 1.41-1.57 (m, 2H), 0.83 (t, J=7.45 Hz, 3H).

Example 1.56: Preparation ofN-[4-(2-Butylamino-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 26)

A mixture ofN-(4-(2-bromoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide(0.0610 g, 0.1418 mmol), n-butylamine (0.01401 mL, 0.1418 mmol) andN,N-diisopropylethylamine (0.07428 mL, 0.4253 mmol) in 1 mL of DMA washeated to 160° C. for 0.5 hours under microwave irradiation in aheavy-walled sealed tube. The reaction mixture was diluted with DMSO andpurified by preparative HPLC. The proper fractions were collected andlyophilized to afford a TFA salt of the title compound as a semi-solidin 97% yield. LCMS m/z=423 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ 10.26 (s,1H), 7.89 (dd, J=8.97, 2.65 Hz, 1H), 7.72 (d, J=2.53 Hz, 1H), 7.39-7.57(m, 4H), 7.23 (d, J=9.09 Hz, 1H), 7.17 (dd, J=8.34, 2.53 Hz, 1H), 6.33(d, J=1.77 Hz, 1H), 4.26 (t, J=5.05 Hz, 2H), 3.84 (s, 3H), 3.70 (s, 3H),3.23-3.35 (m, 2H), 2.77 (d, J=5.05 Hz, 2H), 1.39-1.52 (m, 2H), 1.17-1.30(m, 2H), 0.87 (t, J=7.33 Hz, 3H).

Example 1.57: Preparation ofN-[4-[2-(2-Fluoro-ethylamino)-ethoxy]-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-methoxy-benzamide(Compound 37)

A mixture ofN-(4-(2-bromoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide(0.0645 g, 0.14990 mmol), 2-fluoroethanamine (0.014182 g, 0.22485 mmol)and N,N-diisopropylethylamine (0.07850 mL, 0.44969 mmol) in 1 mL of DMAwas heated to 160° C. for 0.5 hours under microwave irradiation in aheavy-walled sealed tube. The reaction mixture was diluted with DMSO andpurified by preparative HPLC. The proper fractions were collected andlyophilized to afford a TFA salt of the title compound as a semi-solidin 62% yield. LCMS m/z=413 (M+H). ¹H NMR (400 MHz, DMSO-d₆) δ 10.27 (s,1H), 7.89 (dd, J=8.97, 2.65 Hz, 1H), 7.72 (d, J=2.53 Hz, 1H), 7.39-7.60(m, 4H), 7.10-7.29 (m, 2H), 6.33 (d, J=1.77 Hz, 1H), 4.47-4.73 (m, 2H),4.28 (t, J=5.31 Hz, 2H), 3.79-3.86 (m, 3H), 3.63-3.72 (m, 3H), 3.38 (s,2H), 3.20 (s, 2H).

Example 1.58: Preparation of2-(2-(4-Chloro-1-methyl-1H-pyrazol-5-yl)-4-(3-(trifluoromethyl)benzamido)phenoxy)aceticacid (Compound 50) Step A: Preparation of tert-Butyl2-(2-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-(3-(trifluoromethyl)benzamido)phenoxy)acetate

To a solution ofN-(3-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-hydroxyphenyl)-3-(trifluoromethyl)benzamide(0.396 g, 1.00 mmol) and potassium carbonate (0.207 g, 1.50 mmol) inacetone (10 mL) was added tert-butyl bromoacetate (0.215 g, 1.10 mmol).The reaction was stirred at 65° C. for 1 hour and then cooled to roomtemperature and partitioned between ethyl acetate and water. The organiclayer was washed with water (×2) and brine, dried over magnesium sulfateand concentrated to a white solid (0.464 g, 91.0%). LCMS m/z (%)=510(M+H, ³⁵Cl, 30), 512 (M+H, ³⁷Cl, 10), 454 (M-tBu+H, ³⁵Cl, 100). ¹H NMR(400 MHz, CDCl₃) δ 1.47 (s, 9H) 3.80 (s, 3H) 4.52 (s, 2H) 6.87 (d,J=9.09 Hz, 1H) 7.45 (d, J=2.78 Hz, 1H) 7.50 (s, 1H) 7.64 (t, J=7.71 Hz,1H) 7.78-7.89 (m, 2H) 7.94 (s, 1H) 8.07 (d, J=7.83 Hz, 1H) 8.14 (s, 1H).

Step B: Preparation of2-(2-(4-Chloro-1-methyl-1H-pyrazol-5-yl)-4-(3-(trifluoromethyl)benzamido)phenoxy)aceticacid

To a solution of tert-butyl2-(2-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-(3-(trifluoromethyl)benzamido)phenoxy)acetate(0.460 g, 0.902 mmol) in CH₂Cl₂ (5 mL) was added water (0.5 mL) andtrifluoroacetic acid (5 mL, 56 mmol). The resulting solution was stirredfor 18 hours, reduced under vacuum, azeotroped with toluene, andtriturated in ether to give the title compound as a white solid (0.290g, 70.8%). LCMS m/z (%)=454 (M+H, ³⁵Cl, 100), 456 (M+H, ³⁷Cl, 30). ¹HNMR (400 MHz, DMSO-d₆) δ 3.72 (s, 3H) 4.70-4.84 (m, 2H) 7.11 (d, J=9.09Hz, 1H) 7.63 (s, 1H) 7.72 (d, J=2.53 Hz, 1H) 7.79 (t, J=7.83 Hz, 1H)7.87 (dd, J=9.22, 2.65 Hz, 1H) 7.97 (d, J=8.34 Hz, 1H) 8.26 (d, J=8.08Hz, 1H) 8.29 (s, 1H) 10.52 (s, 1H) 13.10 (br. s., 1H).

Step C: Preparation ofN-(3-(4-Chloro-1-methyl-1H-pyrazol-5-yl)-4-(2-(2-methoxyethylamino)-2-oxoethoxy)phenyl)-3-(trifluoromethyl)benzamide(Compound 50)

To a solution of2-(2-(4-chloro-1-methyl-1H-pyrazol-5-yl)-4-(3-(trifluoromethyl)benzamido)phenoxy)aceticacid (0.060 g, 0.13 mmol) and N,N-diisopropylethylamine (0.034 g, 0.26mmol) in dichloromethane (1.3 mL) was added HBTU (0.075 g, 0.20 mmol)followed by 2-methoxyethylamine (0.015 g, 0.2 mmol). After 1.5 hours thereaction was diluted with ethyl acetate, washed with water, 1 M HCl (×3)and brine, dried over magnesium sulfate and concentrated. The residuewas purified by flash chromatography (1:1-1:0 EtOAc/hexane) to give awhite solid (57.0 mg, 84%). LCMS m/z (%)=511 (M+H, ³⁵Cl, 100), 513 (M+H,³⁷Cl, 30). ¹H NMR (400 MHz, CDCl₃) δ 3.35 (s, 3H) 3.39-3.52 (m, 4H) 3.78(s, 3H) 4.52 (s, 2H) 6.60 (br. s., 1H) 7.02 (d, J=9.09 Hz, 1H) 7.55 (s,1H) 7.63-7.67 (m, 2H) 7.74 (dd, J=8.97, 2.91 Hz, 1H) 7.84 (d, J=6.82 Hz,1H) 7.92 (s, 1H) 8.08 (d, J=6.57 Hz, 1H) 8.14 (s, 1H).

Example 1.59: Preparation of3-Fluoro-N-{3-(2-methyl-2H-pyrazol-3-yl)-4-[2-(4-methyl-thiazol-2-ylamino)-ethoxy]-phenyl}-benzamide(Compound 48)

To a solution ofN-(4-(2-bromoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-fluorobenzamide(68.5 mg, 0.164 mmol) and 2-amino-4-methylthiazole (18.7 mg, 0.164 mmol)in DMA (4 mL) was added NaH (56.3 mg, 60% dispersion in mineral oil) andthe reaction was stirred for two hours. The resulting material waspurified by HPLC. The product was dried under reduced pressure to affordthe title compound as a yellow solid (4.0 mg, 5%). LCMS m/z (%)=452(M+H, 100). ¹H NMR (500 MHz, DMSO-d₆) δ 10.32 (bs, 1H), 7.89-7.72 (m,3H), 7.69 (d, J=2.52 Hz, 1H), 7.62-7.56 (m, 1H), 7.48-7.42 (m, 1H), 7.41(d, J=1.89 Hz, 1H), 7.23 (d, J=9.14 Hz, 1H), 6.45 (bs, 1H), 6.23 (d,J=1.89 Hz, 1H), 4.23-4.18 (m, 2H), 3.70-3.65 (m, 2H), 3.65 (s, 3H), 2.16(s, 3H).

Example 1.60: Preparation of3-Fluoro-N-{3-(2-methyl-2H-pyrazol-3-yl)-4-[2-(1H-tetrazol-5-ylamino)-ethoxy]-phenyl}-benzamide(Compound 54)

To a solution ofN-(4-(2-bromoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-fluorobenzamide(61.0 mg, 0.146 mmol) and 5-amino-1H-tetrazole monohydrate (42.5 mg,0.500 mmol) in DMA (4 mL) was added NaH (30 mg, 60% dispersion inmineral oil) and the reaction was stirred for two hours. The resultingmaterial was purified by HPLC. The product was dried under reducedpressure to afford the title compound as a white solid (12.5 mg, 20%).LCMS m/z (%)=423 (M+H, 100).

Example 1.61: Preparation of3-Fluoro-N-{3-(2-methyl-2H-pyrazol-3-yl)-4-[2-(1H-[1,2,4]triazol-3-ylamino)-ethoxy]-phenyl}-benzamide(Compound 42)

To a solution ofN-(4-(2-bromoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-fluorobenzamide(62.3 mg, 0.149 mmol) and 3-amino-1H-1,2,4-triazole (38.8 mg, 0.461mmol) in DMA (4 mL) was added NaH (58.8 mg, 60% dispersion in mineraloil) and the reaction was stirred for two hours. The resulting materialwas purified by HPLC. The product was dried under reduced pressure toafford the title compound as a white solid (30.2 mg, 48%). LCMS m/z(%)=422 (M+H, 100).

Example 1.62: Preparation of3-Bromo-N-[4-(2-methoxy-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 2) Step A: Preparation ofN-(4-(2-methoxyethoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl)acetamide

A mixture of N-(4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)phenyl)acetamide(1.16 g, 5.00 mmol), cesium carbonate (3.26 g, 10.00 mmol), and2-bromoethyl methyl ether (0.666 mL, 7.00 mmol) in 10 mL of DMF washeated to 110° C. for 15 minutes under microwave irradiation in aheavy-walled sealed tube. The solvent was evaporated under reducedpressure, and the residue was taken up in water and extracted threetimes with dichloromethane. The combined extracts were dried with sodiumsulfate, filtered, and evaporated to dryness to afford the titlecompound (1.23 g, 85.0% yield) as a tan solid which was used withoutfurther purification. LCMS m/z (%) 290.1 (M+H, 100%). ¹H NMR (400 MHz,DMSO-d₆) δ 2.01 (s, 3H) 3.22 (s, 3H) 3.55-3.60 (m, 2H) 3.65 (s, 3H)4.06-4.12 (m, 2H) 6.22 (d, J=1.77 Hz, 1H) 7.10 (d, J=9.09 Hz, 1H) 7.43(d, J=2.02 Hz, 1H) 7.49 (d, J=2.78 Hz, 1H) 7.59 (dd, J=8.97, 2.65 Hz,1H) 9.90 (s, 1H).

Step B: Preparation of4-(2-Methoxyethoxy)-3-(2-methyl-2H-pyrazol-3-yl)aniline

To a suspension ofN-(4-(2-methoxyethoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl)acetamide (289mg, 1.0 mmol) in MeOH (3 mL) was added a solution of sodium hydroxide(240 mg, 6.0 mmol) in water (0.4 mL) and the mixture was stirred at 160°C. in a microwave oven. After 30 minutes, the mixture was allowed tocool to room temperature, and the solvent was removed under reducedpressure. The residue was taken up in water, and extracted three timeswith dichloromethane. The extracts were combined, dried with sodiumsulfate, filtered, and evaporated to dryness to afford the titlecompound (231 mg, 93% yield) as a brown oil which was used withoutfurther purification. LCMS m/z (%) 248.1 (M+H, 100%). ¹H NMR (400 MHz,DMSO-d₆) δ 3.19 (s, 3H) 3.48-3.53 (m, 2H) 3.63 (s, 3H) 3.89-3.96 (m, 2H)4.81 (s, 2H) 6.16 (d, J=1.77 Hz, 1H) 6.48 (d, J=3.03 Hz, 1H) 6.62 (dd,J=8.72, 2.91 Hz, 1H) 6.86 (d, J=8.84 Hz, 1H) 7.39 (d, J=1.77 Hz, 1H).

Step C: Preparation of3-Bromo-N-(4-(2-methoxyethoxy)-3-(2-methyl-2H-pyrazol-3-yl)phenyl)benzamide(Compound 2)

A solution of 3-bromobenzoyl chloride (0.06 mmol),N,N-diisopropylethylamine (14 μL, 0.08 mmol), and4-(2-methoxyethoxy)-3-(2-methyl-2H-pyrazol-3-yl)aniline (0.05 mmol) in0.28 mL DMF was agitated on a mechanical shaker for 2 hours. The productwas isolated by RP-HPLC and lyophilized to give the title compound (21.4mg, 96%). LCMS m/z (%)=432.3 (M+H, ⁸¹Br 100.0), 430.3 (M+H, ⁷⁹Br 87.6).

Example 1.63: Preparation of4-Chloro-N-[4-(2-methoxy-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 5)

The title compound was prepared in a similar manner as described inExample 1.62, Step C, 19.1 mg, 95%. LCMS m/z (%)=388.3 (M+H, ³⁷Cl 35.5)386.2 (M+H, ³⁵Cl 100.0).

Example 1.64: Preparation of3-Chloro-N-[4-(2-methoxy-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 7)

The title compound was prepared in a similar manner as described inExample 1.62, Step C, 17.5 mg, 87%. LCMS m/z (%)=388.3 (M+H, ³⁷Cl 29.0)386.2 (M+H, ³⁵Cl 100.0). ¹H NMR (400 MHz, DMSO-d₆) δ 3.23 (s, 3H)3.58-3.62 (m, 2H) 3.69 (s, 3H) 4.12-4.16 (m, 2H) 6.27 (d, J=2.02 Hz, 1H)7.18 (d, J=9.09 Hz, 1H) 7.45 (d, J=1.77 Hz, 1H) 7.57 (t, J=7.96 Hz, 1H)7.64-7.69 (m, 1H) 7.68 (d, J=2.53 Hz, 1H) 7.82 (dd, J=8.84, 2.78 Hz, 1H)7.88-7.93 (m, 1H) 8.00 (t, J=1.89 Hz, 1H) 10.33 (s, 1H).

Example 1.65: Preparation of2-Chloro-N-[4-(2-methoxy-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 9)

The title compound was prepared in a similar manner as described inExample 1.62, Step C, 17.5 mg, 87%. LCMS m/z (%)=388.3 (M+H, ³⁷Cl 36.6)386.2 (M+H, ³⁵Cl 100.0)

Example 1.66: Preparation of4-Fluoro-N-[4-(2-methoxy-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 11)

The title compound was prepared in a similar manner as described inExample 1.62, Step C, 17.2 mg, 90%. LCMS m/z (%)=370.2 (M+H, 100)

Example 1.67: Preparation of3-Fluoro-N-[4-(2-methoxy-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 14)

The title compound was prepared in a similar manner as described inExample 1.62, Step C, 17.4 mg, 91%. LCMS m/z (%)=370.2 (M+H, 100). ¹HNMR (400 MHz, DMSO-d₆) δ 3.23 (s, 3H) 3.58-3.62 (m, 2H) 3.69 (s, 3H)4.11-4.17 (m, 2H) 6.27 (d, J=1.77 Hz, 1H) 7.18 (d, J=9.09 Hz, 1H)7.41-7.48 (m, 2H) 7.55-7.62 (m, 1H) 7.69 (d, J=2.53 Hz, 1H) 7.76 (d,J=11.62 Hz, 1H) 7.78-7.84 (m, 2H) 10.30 (s, 1H).

Example 1.68: Preparation2-Fluoro-N-[4-(2-methoxy-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 17)

The title compound was prepared in a similar manner as described inExample 1.62, Step C, 15.3 mg, 80%. LCMS m/z (%)=370.0 (M+H, 100).

Example 1.69: Preparation ofN-[4-(2-Methoxy-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 20)

The title compound was prepared in a similar manner as described inExample 1.62, Step C, 11.1 mg, 61%. LCMS m/z (%)=352.4 (M+H, 100).

Example 1.70: Preparation of4-Methoxy-N-[4-(2-methoxy-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 25)

The title compound was prepared in a similar manner as described inExample 1.62, Step C, 13.9 mg, 70%. LCMS m/z (%)=382.4 (M+H, 100).

Example 1.71: Preparation of3-Methoxy-N-[4-(2-methoxy-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 30)

The title compound was prepared in a similar manner as described inExample 1.62, Step C, 15.7 mg, 79%. LCMS m/z (%)=382.2 (M+H, 100). ¹HNMR (400 MHz, DMSO-d₆) δ 3.23 (s, 3H) 3.69 (s, 3H) 3.83 (s, 3H) 4.14(dd, J=5.43, 3.66 Hz, 2H) 6.27 (d, J=1.77 Hz, 1H) 7.13-7.19 (m, 2H)7.41-7.49 (m, 3H) 7.50-7.55 (m, 1H) 7.69 (d, J=2.78 Hz, 1H) 7.82 (dd,J=8.97, 2.65 Hz, 1H) 10.20 (s, 1H).

Example 1.72: Preparation of2-Methoxy-N-[4-(2-methoxy-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 35)

The title compound was prepared in a similar manner as described inExample 1.62, Step C, 16.5 mg, 83%. LCMS m/z (%)=382.2 (M+H, 100).

Example 1.73: Preparation ofN-[4-(2-Methoxy-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-4-trifluoromethoxy-benzamide(Compound 40)

The title compound was prepared in a similar manner as described inExample 1.62, Step C, 21.4 mg, 95%. LCMS m/z (%)=436.3 (M+H, 100).

Example 1.74: Preparation ofN-[4-(2-Methoxy-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethoxy-benzamide(Compound 46)

The title compound was prepared in a similar manner as described inExample 1.62, Step C, 21.3 mg, 95%. LCMS m/z (%)=436.3 (M+H, 100). ¹HNMR (400 MHz, DMSO-d₆) δ 3.23 (s, 3H) 3.58-3.63 (m, 2H) 3.69 (s, 3H)4.12-4.17 (m, 2H) 6.27 (d, J=1.77 Hz, 1H) 7.19 (d, J=8.84 Hz, 1H) 7.45(d, J=1.77 Hz, 1H) 7.58-7.64 (m, 1H) 7.65-7.72 (m, 2H) 7.82 (dd, J=8.97,2.65 Hz, 1H) 7.90 (s, 1H) 8.00 (d, J=7.83 Hz, 1H) 10.37 (s, 1H).

Example 1.75: Preparation ofN-[4-(2-Methoxy-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide(Compound 52)

The title compound was prepared in a similar manner as described inExample 1.62, Step C, 20.9 mg, 96%. LCMS m/z (%)=420.4 (M+H, 100).

Example 1.76: Preparation ofN-[4-(2-Methoxy-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-2-trifluoromethyl-benzamide(Compound 57)

The title compound was prepared in a similar manner as described inExample 1.62, Step C, 14.7 mg, 67%. LCMS m/z (%)=420.2 (M+H, 100).

Example 1.77: Preparation of4-Bromo-N-[4-(2-methoxy-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 62)

The title compound was prepared in a similar manner as described inExample 1.62, Step C, 20.3 mg, 91%. LCMS m/z (%)=432.3 (M+H, ⁸¹Br100.0), 430.3 (M+H, ⁷⁹Br 79.9). ¹H NMR (400 MHz, DMSO-d₆) δ 3.23 (s, 3H)3.60 (dd, J=5.31, 3.79 Hz, 2H) 3.68 (s, 3H) 4.11-4.16 (m, 2H) 6.26 (d,J=1.77 Hz, 1H) 7.17 (d, J=9.09 Hz, 1H) 7.45 (d, J=1.77 Hz, 1H) 7.68 (d,J=2.53 Hz, 1H) 7.73-7.77 (m, 2H) 7.81 (dd, J=8.97, 2.65 Hz, 1H)7.87-7.93 (m, 2H) 10.30 (s, 1H).

Example 1.78: Preparation of3-Cyano-N-[4-(2-methoxy-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-benzamide(Compound 81)

The title compound was prepared in a similar manner as described inExample 1.62, Step C, 4.3 mg, 22%. LCMS m/z (%)=377.3 (M+H, 100).

Example 1.79: Preparation ofN-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-ethylamino-2-methyl-propoxy)-phenyl]-3-trifluoromethyl-benzamide(Compound 6) Step A: Preparation ofN-(4-(2-nitro-2-methylpropoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl)-3-(trifluoromethyl)benzamide

Cesium carbonate (815 mg, 2.50 mmol) was added to a solution ofN-(3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxyphenyl)-3-(trifluoromethyl)benzamide(396 mg, 1.00 mmol) and 2-methyl-2-nitropropyl methanesulfonate (276 mg,1.40 mmol) in DMA (2.0 mL), and the mixture was stirred at 160° C. After1 hour, the mixture was allowed to cool to room temperature and pouredinto water, and the resulting suspension was extracted withdichloromethane. The extract was dried with sodium sulfate, filtered,and evaporated to dryness. The crude product was purified by flashchromatography (ethyl acetate-hexanes 1:2) to afford the title compound(338 mg, 68%) as a yellow oil. LCMS m/z (%)=499.5 (M+H, ³⁷Cl 31.5),497.4 (M+H, ³⁵Cl 100.0). ¹H NMR (400 MHz, CDCl₃) δ 1.51 (s, 3H) 1.57 (s,3H) 3.64 (s, 3H) 4.01 (d, J=9.85 Hz, 1H) 4.49 (d, J=9.85 Hz, 1H) 7.08(d, J=8.84 Hz, 1H) 7.49 (d, J=2.53 Hz, 1H) 7.51 (s, 1H) 7.65 (t, J=7.71Hz, 1H) 7.79-7.89 (m, 3H) 8.07 (d, J=7.83 Hz, 1H) 8.13 (s, 1H).

Step B: Preparation ofN-(4-(2-amino-2-methylpropoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl)-3-(trifluoromethyl)benzamide

Acetyl chloride (388 μl, 5.44 mmol) was added dropwise to a solution ofN-(4-(2-nitro-2-methylpropoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl)-3-(trifluoromethyl)benzamide(270 mg, 0.544 mmol) in methanol (5.0 mL). Zinc dust (356 mg, 5.44 mmol)was added, and the mixture was stirred at 23° C. After 1 hour, themixture was filtered and the filtrate was evaporated to dryness. Theresidue was taken up in ammonium hydroxide (35%), diluted with water andextracted with ethyl acetate. The organic layer was washed with brine,dried with sodium sulfate, filtered, and evaporated to dryness to affordthe title compound as a colorless foam which was used without furtherpurification. LCMS m/z (%) 469.4 (M+H, ³⁷Cl 46.9), 467.2 (M+H, ³⁵Cl86.1), 452.2 (51.6%), 450.1 (100.0%).

Step C: Preparation ofN-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-ethylamino-2-methyl-propoxy)-phenyl]-3-trifluoromethyl-benzamide(Compound 6)

Sodium triacetoxyborohydride (34.2 mg, 161 μmol) was added to a solutionofN-(4-(2-amino-2-methylpropoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl)-3-(trifluoromethyl)benzamide(53.8 mg, 115 μmol) and acetaldehyde (5.08 mg, 115 μmol) in THF (0.5mL), and the mixture was stirred at room temperature. After 4 hours, thereaction was quenched with saturated sodium bicarbonate and extractedwith dichloromethane. The extract was evaporated to dryness, the residuewas redissolved in methanol, and the product was isolated by preparativeHPLC. The trifluoroacetate salt was dissolved in a mixture of ethylacetate and saturated sodium bicarbonate. The organic layer was washedwith brine, dried with sodium sulfate, and evaporated to dryness toafford the title compound (12.5 mg, 22%). LCMS m/z (%)=497.5 (M+H, ³⁷Cl45.4), 495.3 (M+H, ³⁵Cl 100.0%). ¹H NMR (400 MHz, MeOH-d₄) δ 1.00 (t,J=7.07 Hz, 3H) 1.07 (s, 6H) 2.42-2.51 (m, 2H) 3.71 (s, 3H) 3.85-3.88 (m,J=9.35 Hz, 1H) 3.90 (d, J=9.09 Hz, 1H) 7.22 (d, J=9.09 Hz, 1H) 7.58 (s,1H) 7.67 (d, J=2.78 Hz, 1H) 7.73 (t, J=7.83 Hz, 1H) 7.85-7.92 (m, 2H)8.21 (d, J=7.83 Hz, 1H) 8.27 (s, 1H).

Example 1.80: Preparation ofN-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-(2-methyl-2-propylamino-propoxy)-phenyl]-3-trifluoromethyl-benzamide(Compound 67)

Sodium triacetoxyborohydride (34 mg, 161 μmol) was added to a solutionofN-(4-(2-amino-2-methylpropoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl)-3-(trifluoromethyl)benzamide(53.8 mg, 115 μmol) and propionaldehyde (6.7 mg, 115 μmol) in THF (0.5mL), and the mixture was stirred at room temperature. After 4 hours, thereaction was quenched with saturated sodium bicarbonate and extractedwith dichloromethane. The extract was evaporated to dryness, the residuewas redissolved in methanol, and the products were isolated bypreparative HPLC. Product containing fractions were combined andconcentrated in a vacuum centrifuge to one fourth of the originalvolume. The solution was made alkaline with saturated sodiumbicarbonate, the product was extracted with dichloromethane, and theextract was evaporated to dryness. The residue was dissolved in asolution of acetyl chloride (16 μl, 230 μmol) in methanol (1 mL) andevaporated to dryness. The residue was dissolved in water andlyophilized to give the title compound (30 mg, 48%) as the hydrochloridesalt. LCMS m/z (%)=511.4 (M+H, ³⁷Cl 60.5), 509.3 (M+H, ³⁵Cl 100.0%). ¹HNMR (400 MHz, DMSO-d₆) δ 0.87 (t, J=7.45 Hz, 3H) 1.26 (s, 6H) 1.46-1.58(m, 2H) 2.53-2.64 (m, 2H) 3.65 (s, 3H) 4.06 (d, J=10.36 Hz, 1H) 4.16 (d,J=10.36 Hz, 1H) 7.33 (d, J=9.09 Hz, 1H) 7.69 (s, 1H) 7.73 (d, J=2.78 Hz,1H) 7.80 (t, J=7.83 Hz, 1H) 7.94-8.02 (m, 2H) 8.28 (d, J=8.34 Hz, 1H)8.31 (s, 1H) 8.65 (s, 2H) 10.59 (s, 1H).

Example 1.81: Preparation ofN-[4-(2-Butylamino-2-methyl-propoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-phenyl]-3-trifluoromethyl-benzamide(Compound 75)

Sodium triacetoxyborohydride (34 mg, 161 μmol) was added to a solutionofN-(4-(2-amino-2-methylpropoxy)-3-(4-chloro-2-methyl-2H-pyrazol-3-yl)phenyl)-3-(trifluoromethyl)benzamide(53.8 mg, 115 μmol) and butyraldehyde (8 mg, 115 μmol) in THF (0.5 mL),and the mixture was stirred at room temperature. After 4 hours, thereaction was quenched with saturated sodium bicarbonate and extractedwith dichloromethane. The extract was evaporated to dryness, the residuewas redissolved in methanol, and the products were isolated bypreparative HPLC. Product containing fractions were combined andconcentrated in a vacuum centrifuge to one fourth of the originalvolume. The solution was made alkaline with saturated sodiumbicarbonate, the product was extracted with dichloromethane, and theextract was evaporated to dryness. The residue was dissolved in asolution of acetyl chloride (16 μl, 230 μmol) in methanol (1 mL) andevaporated to dryness. The residue was dissolved in water andlyophilized to give the title compound (24 mg, 37%) as the hydrochloridesalt. LCMS m/z (%)=553.6 (M+H, ³⁷Cl 34.5), 551.6 (M+H, ³⁵Cl 100.0%). ¹HNMR (400 MHz, DMSO-d₆) δ 0.88 (t, J=7.33 Hz, 3H) 1.21-1.34 (m, 2H) 1.26(s, 6H) 1.40-1.54 (m, 2H) 2.55-2.71 (m, 2H) 3.65 (s, 3H) 4.05 (d,J=10.36 Hz, 1H) 4.15 (d, J=10.36 Hz, 1H) 7.32 (d, J=9.09 Hz, 1H) 7.68(s, 1H) 7.72 (d, J=2.78 Hz, 1H) 7.80 (t, J=7.71 Hz, 1H) 7.93-8.01 (m,2H) 8.27 (d, J=7.83 Hz, 1H) 8.30 (s, 1H) 8.58 (s, 2H) 10.58 (s, 1H).

Example 2

Receptor Expression

A. pCMV

Although a variety of expression vectors are available to those in theart, it is preferred that the vector utilized be pCMV. This vector wasdeposited with the American Type Culture Collection (ATCC) on Oct. 13,1998 (10801 University Blvd., Manassas, Va. 20110-2209 USA) under theprovisions of the Budapest Treaty for the International Recognition ofthe Deposit of Microorganisms for the Purpose of Patent Procedure. TheDNA was tested by the ATCC and determined to be viable. The ATCC hasassigned the following deposit number to pCMV: ATCC #203351.

B. Transfection Procedure

For the IP accumulation assay (Example 3), HEK293 cells were transfectedwhile for the DOI binding assay (Example 4) COS7 cells were transfected.Several protocols well known in the art can be used to transfect cells.The following protocol is representative of the transfection proceduresused herein for COS7 or 293 cells.

On day one, COS-7 cells were plated onto 24 well plates, usually 1×10⁵cells/well or 2×10⁵ cells/well, respectively. On day two, the cells weretransfected by first mixing 0.25 μg cDNA in 50 μL serum-free DMEM/welland then 2 μL lipofectamine in 50 μL serum-free DMEM/well. The solutions(“transfection media”) were gently mixed and incubated for 15-30 minutesat room temperature. The cells were washed with 0.5 mL PBS and then 400μL of serum free media was mixed with the transfection media and addedto the cells. The cells were then incubated for 3-4 hours at 37° C./5%CO₂. Then the transfection media was removed and replaced with 1 mL/wellof regular growth media.

For 293 cells, on day one, 13×10⁶ 293 cells per 150 mm plate were platedout. On day two, 2 mL of serum OptimemI (Invitrogen Corporation) wasadded per plate followed by addition of 60 μL of lipofectamine and 16 μgof cDNA. Note that lipofectamine must be added to the OptimemI and mixedwell before addition of cDNA. While complexes between lipofectamine andthe cDNA are forming, media was carefully aspirated and cells weregently rinsed with 5 mL of OptimemI media followed by carefulaspiration. Then 12 mL of OptimemI was added to each plate and 2 mL oftransfection solution was added followed by a 5 hour incubation at 37°C. in a 5% CO₂ incubator. Plates were then carefully aspirated and 25 mLof Complete Media were added to each plate and cells were then incubateduntil used.

Example 3

Inositol Phosphate (IP) Accumulation Assays

A. 5-HT_(2A) Receptor

Compounds of the invention are tested for their ability to activate a5-HT_(2A) receptor clone using an IP accumulation assay. Briefly, HEK293cells are transiently transfected with a pCMV expression vectorcontaining a human 5-HT_(2A) receptor (for the sequence of the receptorsee U.S. Pat. No. 6,541,209, SEQ ID NO:24) as described in Example 2. AnIP accumulation assay is performed as described below.

B. Constitutively Active 5-HT_(2A) Receptor

Compounds of the invention are tested for their ability to inhibit aconstitutively active 5-HT_(2A) receptor clone using an IP accumulationassay. Briefly, 293 cells are transiently transfected with a pCMVexpression vector containing a constitutively active human 5-HT_(2A)receptor (for the sequence of the receptor see U.S. Pat. No. 6,541,209,SEQ ID NO:30) as described in Example 2. The constitutively active human5-HT_(2A) receptor contained the human 5-HT_(2A) receptor described inpart A except that intracellular loop 3 (IC3) and the cytoplamic tailare replaced by the corresponding human INI 5-HT2C cDNA. An IPaccumulation assay is performed as described below.

C. IP Accumulation Assay Protocol

On the day after transfections, media is removed and the cells arewashed with 5 mL PBS followed by careful aspiration. Cells are thentrypsinized with 2 mL of 0.05% trypsin for 20-30 seconds followed byaddition of 10 mL of warmed media, gently titurated to dissociate cells,and an additional 13 mL of warmed media is gently added. Cells are thencounted and 55,000 cells are added to 96-well sterile poly-D-lysinetreated plates. Cells are allowed to attach over a six hour incubationat 37° C. in a 5% CO₂ incubator. Media is then carefully aspirated and100 μL of warm inositol-free media plus 0.5 μCi ³H-inositol is added toeach well and the plates are incubated for 18-20 hours at 37° C. in a 5%CO₂ incubator.

On the next day, media is carefully aspirated and then 0.1 mL of assaymedium is added containing inositol-free/serum free media, 10 μMpargyline, 10 mM lithium chloride, and test compound at indicatedconcentrations. The plates are then incubated for three hours at 37° C.and then wells are carefully aspirated. Then 200 μL of ice-cold 0.1Mformic acid is added to each well. Plates can then be frozen at thispoint at −80° C. until further processed. Frozen plates are then thawedover the course of one hour, and the contents of the wells(approximately 220 μL) are placed over 400 μL of washed ion-exchangeresin (AG 1-X8) contained in a Multi Screen Filtration plate andincubated for 10 minutes followed by filtration under vacuum pressure.Resin is then washed nine times with 200 μL of water and then tritiatedinositol phosphates (IP, IP2, and IP3) are eluted into a collectingplate by the addition of 200 μl of 1M ammonium formate and an additional10 minute incubation. The eluant is then transferred to 20 mLscintillation vials, 8 mL of SuperMix or Hi-Safe scintillation cocktailsis added, and vials are counted for 0.5-1 minutes in a Wallac 1414scintilation counter.

Example 4

Binding Assays

Compounds of the invention were tested for their ability to bind to a5-HT_(2A) receptor clone membrane preparation using a radioligandbinding assay. Briefly, COS cells were transiently transfected with apCMV expression vector containing a human 5-HT_(2A) receptor (for thesequence of the receptor see U.S. Pat. No. 6,541,209, SEQ ID NO:24) asdescribed in Example 2.

A. Preparation of Crude Membrane Preparations for Radioligand BindingAssays

COS7 cells transfected with recombinant human 5-HT_(2A) receptors werecultured for 48 hr post transfection, collected, washed with ice-coldphosphate buffered saline, pH7.4 (PBS), and then centrifuged at 48,000×gfor 20 min at 4° C. The cell pellet was then resuspended in wash buffercontaining 20 mM HEPES pH 7.4 and 0.1 mM EDTA, homogenized on ice usinga Brinkman polytron, and recentrifuged at 48,000×g for 20 min. at 4° C.The resultant pellet was then resuspended in 20 mM HEPES, pH 7.4,homogenized on ice, and centrifuged (48,000×g for 20 min at 4° C.).Crude membrane pellets were stored at −80° C. until used for radioligandbinding assays.

B. [¹²⁵I]DOI Radioligand Binding Assay

Radioligand binding assays for human 5-HT_(2A) receptor was conductedusing the 5-HT₂ agonist [¹²⁵I]DOI as radioligand. To define nonspecificbinding, 10 μM DOI was used for all assays. For competitive bindingstudies, 0.5 nM [¹²⁵I]DOI was used and compounds were assayed over arange of 0.01 nM to 10 μM. Assays were conducted in a total volume of200 μl in 96-well Perkin Elmer GF/C filter plates in assay buffer (50 mMTris-HCl, pH 7.4, 0.5 mM EDTA, 5 mM MgCl₂, and 10 μM pargyline). Assayincubations were performed for 60 min at room temperature and wereterminated by rapid filtration under vacuum pressure of the reactionmixture over Whatman GF/C glass fiber filters presoaked in 0.5% PEIusing a Brandell cell harvestor. Filters were then washing several timeswith ice-cold wash buffer (50 mM Tris-HCl, pH 7.4). Plates were thendried at room temperature and counted in a Wallac microBetascintillation counter. Certain compounds of the present invention andtheir corresponding activity values are shown in the following table.

Compound No. IC₅₀ DOI Binding Assay (nM) 15 0.082 68 0.51 52 4.4 50 52Certain other compounds of the invention had activity values rangingfrom about 10 μM to about 0.10 nM in this assay.

Example 5

In Vitro Human Platelet Aggregation Assays

Compounds of the invention were tested for their ability to aggregatehuman platelets. Aggregation assays were performed using a Chrono-LogOptical aggregometer model 410. Human blood (˜100 mL) was collected fromhuman donors into glass Vacutainers containing 3.8% sodium citrate(light blue tops) at room temperature. Platelet rich plasma (PRP) wasisolated via centrifugation at 100 g for 15 min at room temperature.After removal of the aqueous PRP layer, the platelet poor plasma (PPP)was prepared via high speed centrifugation at 2400 g for 20 min.Platelets were counted and their concentration was set to 250,000cells/μl by dilution with PPP. Aggregation assays were conductedaccording to the manufacturer's specifications. Briefly, a suspension of450 μl PRP was stirred in a glass cuvette (1200 rpm) and, after baselinewas established, 1 μM ADP followed by either saline or 1 μM 5HT andcompound of interest (at desired concentrations) were added and theaggregation response recorded. The concentration of ADP used causesapproximately 10-20% of maximal aggregation. The 5-HT concentrationcorresponded to the concentration which produced maximal potentiation.Percent inhibition of aggregation was calculated from the maximumdecrease in optical density of the controls and of the samplescontaining inhibitors. Only the synergistic effect was assessed. Certaincompounds of the invention had activity values ranging from about 10 μMto about 5 nM in this assay.

Example 6

Efficacy of Compounds of the Invention in the Attenuation of DOI-InducedHypolocomotion in Rats.

In this example, compounds of the invention can be tested for inverseagonist activity by determining whether these compounds could attenuateDOI-induced hypolocomotion in rats in a novel environment. DOI is apotent 5-HT_(2A/2C) receptor agonist that crosses the blood-brainbarrier. The standard protocol used is described briefly below.

Animals:

Male Sprague-Dawley rats weighing between 200-300 g are used for alltests. Rats are housed three to four per cage. These rats are naïve toexperimental testing and drug treatment. Rats are handled one to threedays before testing to acclimate them to experimental manipulation. Ratsare fasted overnight prior to testing.

Compounds:

(R)-DOI HCl (C₁₁H₁₆INO₂.HCl) can be obtained from Sigma-Aldrich, and isdissolved in 0.9% saline. Compounds of the invention are dissolved in100% PEG400. DOI is injected s.c. in a volume of 1 mL/kg, whilecompounds of the invention are administered p.o. in a volume of 2 mL/kg.

Procedure:

The “Motor Monitor” (Hamilton-Kinder, Poway, Calif.) is used for allactivity measurement. This apparatus recorded rears using infraredphotobeams.

Locomotor activity testing is conducted during the light cycle(0630-1830) between 9:00 a.m. and 4:00 p.m. Animals are allowed 30 minacclimation to the testing room before testing began.

In determining the effects of compounds of the invention on DOI-inducedhypoactivity, animals are first injected with vehicle or the compound ofthe invention (50 μmol/kg) in their home cages. Sixty minutes later,saline or DOI (0.3 mg/kg salt) is injected. 10 min after DOIadministration, animals are placed into the activity apparatus andrearing activity is measured for 10 minutes.

Statistics and Results:

Results (total rears over 10 minutes) are analyzed by t-test. P<0.05 isconsidered significant.

Example 7

In Vitro Binding of 5-HT_(2A) Receptor

Animals:

Animals (Sprague-Dawley rats) are sacrificed and brains are rapidlydissected and frozen in isopentane maintained at −42° C. Horizontalsections are prepared on a cryostat and maintained at −20° C.

LSD Displacement Protocol:

Lysergic acid diethylamide (LSD) is a potent 5-HT_(2A) receptor anddopamine D₂ receptor ligand. An indication of the selectivity ofcompounds for either or both of these receptors involves displacement ofradiolabeled-bound LSD from pre-treated brain sections. For thesestudies, radiolabeled ¹²⁵I-LSD (NEN Life Sciences, Boston, Mass.,Catalogue number NEX-199) can be utilized; spiperone (RBI, Natick, Mass.Catalogue number s-128) a 5-HT_(2A) receptor and dopamine D₂ receptorantagonist, can also utilized. Buffer consists of 50 nanomolar TRIS-HCl,pH 7.4.

Brain sections are incubated in (a) Buffer plus 1 nanomolar ¹²⁵I-LSD;(b) Buffer plus 1 nanomolar ¹²⁵I-LSD and 1 micromolar spiperone; orBuffer plus 1 nanomolar ¹²⁵I-LSD and 1 micromolar Compound of interestfor 30 minutes at room temperature. Sections are then washed 2×10minutes at 4° C. in Buffer, followed by 20 seconds in distilled H₂O.Slides are then air-dried.

After drying, sections are apposed to x-ray film (Kodak Hyperfilm) andexposed for 4 days.

Example 8

Serotonin 5-HT_(2A) Receptor Occupancy Studies in Monkey

In this example, the 5-HT_(2A) receptor occupancy of a compound of theinvention can be measured. The study can be carried out in rhesusmonkeys using PET and ¹⁸F-altanserin.

Radioligand:

The PET radioligand used for the occupancy studies is ¹⁸F-altanserin.Radiosynthesis of ¹⁸F-altanserin is achieved in high specific activitiesand is suitable for radiolabeling 5-HT_(2A) receptors in vivo (seeStaley et al., Nucl. Med. Biol., 28:271-279 (2001) and references citedwithin). Quality control issues (chemical and radiochemical purity,specific activity, stability etc) and appropriate binding of theradioligand are verified in rat brain slices prior to use in PETexperiments.

Drug Doses and Formulations:

Briefly, the radiopharmaceutical is dissolved in sterile 0.9% saline, pHapprox 6-7. The compounds of the invention are dissolved in 60% PEG400-40% sterile saline on the same day of the PET experiment.

Serotonin 5-HT_(2A) occupancy studies in humans have been reported forM100,907 (Grunder et al., Neuropsychopharmacology, 17:175-185 (1997),and Talvik-Lofti et al., Psychopharmacology, 148:400-403 (2000)). Highoccupancies of the 5-HT_(2A) receptors have been reported for variousoral doses (doses studied ranged from 6 to 20 mg). For example, anoccupancy of >90% was reported for a dose of 20 mg (Talvik-Lofti et al.,supra), which translates to approx. 0.28 mg/kg. It may therefore beanticipated that an i.v. dose of 0.1 to 0.2 mg/kg of M100,907 is likelyto provide high receptor occupancy. A 0.5 mg/kg dose of a Compound ofthe invention can be used in these studies.

PET Experiments:

The monkey is anesthetized by using ketamine (10 mg/kg) and ismaintained using 0.7 to 1.25% isoflurane. Typically, the monkey has twoi.v. lines, one on each arm. One i.v. line is used to administer theradioligand, while the other line is used to draw blood samples forpharmacokinetic data of the radioligand as well as the cold drugs.Generally, rapid blood samples are taken as the radioligand isadministered which then taper out by the end of the scan. A volume ofapproximately 1 mL of blood is taken per time point, which is spun down,and a portion of the plasma is counted for radioactivity in the blood.

An initial control study is carried out in order to measure baselinereceptor densities. PET scans on the monkey are separated by at leasttwo weeks. Unlabeled Compound of the invention is administeredintravenously, dissolved in 80% PEG 400:40% sterile saline.

PET Data Analysis:

PET data are analyzed by using cerebellum as the reference region andusing the distribution volume region (DVR) method. This method has beenapplied for the analysis of ¹⁸F-altanserin PET data in nonhuman primateand human studies (Smith et al., Synapse, 30:380-392 (1998).

Example 9

The Effect of Compounds of the Invention and Zolpidem on Delta Power inRats

In this example, the effect of Compounds of the invention on sleep andwakefullness can be compared to the reference drug zolpidem. Drugs areadministered during the middle of the light period (inactivity period).

Briefly, Compounds of the invention are tested for their effects onsleep parameters and are compared to zolpidem (5.0 mg/kg, Sigma, St.Louis, Mo.) and vehicle control (80% Tween 80, Sigma, St. Louis, Mo.). Arepeated measures design is employed in which each rat is to receiveseven separate dosings via oral gavage. The first and seventh dosingsare vehicle and the second through sixth are the test compounds andzolpidem given in counter-balanced order. Since all dosings areadministered while the rats are connected to the recording apparatus,60% CO₂/40% O₂ gas is employed for light sedation during the oral gavageprocess. Rats are fully recovered within 60 seconds following theprocedure. A minimum of three days elapses between dosings. In order totest the effect of the compounds on sleep consolidation, dosing occursduring the middle of the rats' normal inactive period (6 hours followinglights on). Dosing typically occurs between 13:15 and 13:45 using a 24hour notation. All dosing solutions are made fresh on the day of dosing.Following each dosing, animals are continuously recorded until lightsout the following day (˜30 hours).

Animal Recording and Surgical Procedures:

Animals are housed in a temperature controlled recording room under a12/12 light/dark cycle (lights on at 7:00 am) and have food and wateravailable ad libitum. Room temperature (24±2° C.), humidity (50±20%relative humidity) and lighting conditions are monitored continuouslyvia computer. Drugs are administered via oral gavage as described above,with a minimum of three days between dosings. Animals are inspecteddaily in accordance with NIH guidelines.

Eight male Wistar rats (300+25 g; Charles River, Wilmington, Mass.) areprepared with chronic recording implants for continuouselectroencephalograph (EEG) and electromyograph (EMG) recordings. Underisoflurane anesthesia (1-4%), the fur is shaved from the top of theskull and the skin was disinfected with Betadine and alcohol. A dorsalmidline incision is made, the temporalis muscle retracted, and the skullcauterized and thoroughly cleaned with a 2% hydrogen peroxide solution.Stainless steel screws (#000) are implanted into the skull and served asepidural electrodes. EEG electrodes are positioned bilaterally at +2.0mm AP from bregma and 2.0 mm ML and at −6.0 mm AP and 3.0 mm ML.Multi-stranded twisted stainless steel wire electrodes are suturedbilaterally in the neck muscles for recording of the EMG. EMG and EEGelectrodes are soldered to a head plug connector that was affixed to theskull with dental acrylic. Incisions are closed with suture (silk 4-0)and antibiotics administered topically. Pain is relieved by along-lasting analgesic (Buprenorphine) administered intramuscularly oncepost-operatively. Post-surgery, each animal is placed in a clean cageand observed until it is recovered. Animals are permitted a minimum ofone week post-operative recovery before study.

For sleep recordings, animals are connected via a cable and acounter-balanced commutator to a Neurodata model 15 data collectionsystem (Grass-Telefactor, West Warwick, R.I.). The animals are allowedan acclimation period of at least 48 hours before the start of theexperiment and are connected to the recording apparatus continuouslythroughout the experimental period except to replace damaged cables. Theamplified EEG and EMG signals are digitized and stored on a computerusing SleepSign software (Kissei Comtec, Irvine Calif.).

Data Analysis:

EEG and EMG data are scored visually in 10 second epochs for waking (W),REMS, NREMS. Scored data are analyzed and expressed as time spent ineach state per half hour. Sleep bout length and number of bouts for eachstate are calculated in hourly bins. A “bout” consists of a minimum oftwo consecutive epochs of a given state. EEG delta power (0.5-3.5 Hz)within NREMS is also analyzed in hourly bins. The EEG spectra duringNREMS are obtained offline with a fast Fourier transform algorithm onall epochs without artifact. The delta power is normalized to theaverage delta power in NREMS between 23:00 and 1:00, a time when deltapower is normally lowest.

Data are analyzed using repeated measures ANOVA. Light phase and darkphase data are analyzed separately. Both the treatment effect withineach rat and the time by treatment effect within each rat is analyzed.Since two comparisons are made, a minimum value of P<0.025 is requiredfor post hoc analysis. When statistical significance is found from theANOVAs, t-tests are performed comparing all compounds to vehicle and thetest compounds to zolpidem.

Example 10

Efficacy of Compounds of the Invention in the Inhibition of JC VirusInfection of Human Glial Cells

A compound of the invention can be shown to inhibit JC virus infectionof human glial cells using the in vitro model of Elphick et al. [Science(2004) 306:1380-1383], essentially as described briefly here.

Cells and JC Virus

The human glial cell line SVG (or a suitable subclone thereof, such asSVG-A) is used for these experiments. SVG is a human glial cell lineestablished by transformation of human fetal glial cells by an origindefective SV40 mutant [Major et al., Proc. Natl. Acad. Sci. USA (1985)82:1257-1261]. SVG cells are cultured in Eagle's minimum essentialmedium (Mediatech Inc., Herndon, Va.) supplemented with 10%heat-inactivated fetal bovine serum, and kept in a humidified 37° C. 5%CO₂ incubator.

The Mad-1/SVEΔ strain of JC virus [Vacante et al., Virology (1989)170:353-361] is used for these experiments. While the host range of JCvirus is typically limited to growth in human fetal glial cells, thehost range of Mad-1/SVEΔ extends to human kidney and monkey cell types.Mad-1/SVEΔ is propagated in HEK cells. Virus titer is measured byhemagglutination of human type O erythrocytes.

Assay for Inhibition of JC Virus Infection

SVG cells growing on coverslips are pre-incubated at 37° C. for 45 minwith or without the compound of the invention diluted in mediacontaining 2% FCS. By way of illustration and not limitation, thecompound of the invention is used at a concentration of about 1 nM toabout 100 μM, at a concentration of about 10 nM to about 100 μM, at aconcentration of about 1 nM to about 10 μM, or at a concentration ofabout 10 nM to about 10 μM.

JC virus (Mad-1/SVEΔ) is then added at an MOI of 1.0 and the cells areincubated for 1 hr at 37° C. in the continued presence of the compoundof the invention. The cells are then washed 3× in PBS and fed withgrowth media containing the compound of the invention. At 72 hrpost-infection, V antigen positive cells are scored by indirectimmunofluorescence (see below). Controls include the addition of thecompound of the invention at 24 and 48 h post-infection. The percentageof infected cells in untreated cultures is set at 100%.

Indirect Immunofluorescence

For indirect immunofluorescence analysis of V antigen expression, SVGcells growing on coverslips are fixed in ice cold acetone. To detect Vantigen expression, the cells are then incubated for 30 min at 37° C.with a 1:10 dilution of hybridoma supernatant from PAB597. The PAB597hybridoma produces a monoclonal antibody against the SV40 capsid proteinVP1 which has been shown to cross-react with JC virus VP1. The cells arethen washed and incubated with goat anti-mouse Alexa Fluor 488 secondaryantibody for an additional 30 min. After a final wash, the cells arecounterstained with 0.05% Evan's blue, mounted onto glass slides using90% glycerol in PBS and visualized on Nikon E800 epifluorescent scope.Images are captured using a Hamamatsu digital camera and analyzed usingImprovision software.

Example 11

In Vitro Dog Platelet Aggregation Assays

Approximately 50 mL of blood is pooled from 3 male beagles. The protocolfor analyzing the effects of compounds on platelet aggregation areidentical to those used for human platelets (see Example 5, supra)except 5 μM ADP and 2 μM 5-HT were used to stimulate amplification ofplatelet aggregation.

Example 12

Ex-Vivo Dog Whole Blood Aggregation

One hour following PO dosing with a test compound whole blood wascollected from male beagle dogs in a 5 mL vacutainer with exogenousheparin (5 U/mL) added to vacutainer. Aggregation studies were evaluatedby using whole blood Aggregometer (Chronolog Corp.). Briefly, wholeblood (400 uL) was added to saline (600 uL) with constant stirring andactivated with 5 ug of Collagen (Chronolog Corp.). The serotoninresponse was obtained by adding 5-HT (Sigma) to final concentration of2.5 μM. Results: Selected compounds were tested for antiplateletaggregation activity after single bolus oral dosing. The dose thatafforded maximal inhibition of 5-HT amplified platelet aggregation wasidentified and used for comparison.

Example 13

Rat In Vivo Thrombosis, Bleeding, Aggregation, PK Assay

Thrombosis Formation and Bleeding Time:

This model concomitantly measures thrombus formation, bleeding time,platelet aggregation and drug exposure in a single live dosed rat. Testcompounds are administered to male rats (weighing 250-350 g) via POinjection at varying concentrations depending on compound potencyranging from 1 mpk-100 mpk. Animals are then anesthetized using Nembutalapproximately 30 min post PO. Once the animal is fully anesthetizedusing approved surgical techniques the animal's right femoral artery isisolated in 2 different sections approximately 4-6 mm in length, onearea for probe placement and one for Ferric Chloride patch positioning.The artery is then allowed to stabilize to allow recovery from thesurgery. During stabilization the animal is then intubated and placed ona ventilator (Harvard Apparatus, Inc.) at 75 strokes/min with a volumeof 2.5 cubic cm. Following intubation and after stabilization a microarterial probe (Transonic Systems, Inc) is then placed on the distalisolated femoral artery. Once the probe is in place the flow ismonitored using a Powerlab recording system (AD Instruments) to monitorrate of pulsatile flow. A small piece of filter paper soaked in 30%ferric chloride is placed on the area of the artery upstream of theprobe for 10 min. After 5 min of Ferric Choloride patch placement thelast 3 mm of the rat's tail is removed. The tail is then placed in asaline filled glass vial at 37 degree and the time it took for bleedingto stop is recorded. After the Ferric chloride patch is removed the flowis recorded until the artery is occluded and time to occlusion isrecorded.

Whole Blood Aggregation and PK:

Following measurement of bleeding and time to occlusion 5 mL of blood isobtained for ex-vivo aggregation analysis by cardiac puncture in heparin(5 U/mL). An additional 500 μL of blood is collected in a separatevacutainer for PK analysis (plasma drug concentration). Ex-vivoaggregation studies are evaluated by using whole blood Aggregometer(Chronolog Corp.). Briefly, whole blood (400 μL) is added to saline (600μL) with constant stirring and activated with 2.55 μg of Collagen(Chronolog Corp.). The serotonin response is obtained by adding 5-HT(Sigma) to final concentration of 2.5 μM. Results: Test compounds orreference compounds with acceptable levels of binding to rat 5-HT2Areceptors are evaluated for effects of thrombus formation, bleeding andplatelet activity in a single model. This allows for the most accuratedemonstration of separation of the test compound effects on plateletmediated thrombus formation from effects on bleeding.

Those skilled in the art will recognize that various modifications,additions, substitutions, and variations to the illustrative examplesset forth herein can be made without departing from the spirit of theinvention and are, therefore, considered within the scope of theinvention. All documents referenced above, including, but are notlimited to, printed publications, and provisional and regular patentapplications, are incorporated herein by reference in their entirety.

What is claimed is:
 1. A method for treating a 5-HT_(2A) associateddisorder in an individual comprising administering to the individual inneed thereof a pharmaceutical composition comprising a therapeuticallyeffective amount of a compound of Formula (Ia);

or a pharmaceutically acceptable salt, hydrate or solvate thereof, and apharmaceutically acceptable carrier, wherein: V is O or NH; W is C₁₋₄alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8substituents selected independently from the group consisting of C₁₋₃alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₃₋₇ cycloalkyl, C₁₋₃ haloalkyl,halogen, and oxo; Q is —NR^(4a)R^(4b) or —OR^(4c), wherein: R^(4a) is H,C₁₋₁₂ acyl, carbo-C₁₋₁₂-alkoxy, or C(═O)O-aryl, wherein said C₁₋₁₂ acyl,carbo-C₁₋₁₂-alkoxy, and —C(═O)O-aryl is optionally substituted with 1,2, 3, 4, or 5 substituents selected independently from the groupconsisting of C₁₋₅ acyloxy, C₁₋₆ alkylcarboxamide, amino, C₁₋₆alkylamino, C₂₋₅ dialkylamino, C₁₋₆ alkylimino, C₁₋₆ alkylsulfinyl, C₁₋₆alkylsulfonyl, C₁₋₆ alkylthio, halogen, nitro, and phenyl; R^(4b) isC₁₋₆ alkyl, aryl, C₃₋₇ cycloalkyl, C₁₋₆ haloalkyl, heterocyclyl, orheteroaryl, wherein each is optionally substituted with 1, 2, 3, 4, or 5substituents selected independently from the group consisting of C₁₋₅acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₅ alkyl, C₁₋₆alkylamino, C₂₋₅ dialkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl, imino, nitro,sulfonamide and phenyl; and R^(4c) is H, or R^(4c) is C₁₋₆ alkyl, C₁₋₁₂acyl, aryl, C₃₋₇ cycloalkyl, C₁₋₆ haloalkyl, heterocyclyl, orheteroaryl, wherein each is optionally substituted with 1, 2, 3, 4, or 5substituents selected independently from the group consisting of C₁₋₅acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₅ alkyl, C₁₋₆alkylamino, C₂₋₅ dialkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₆ alkylamino, C₂₋₅ dialkylamino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,heterocyclyl, hydroxyl, imino, nitro, sulfonamide and phenyl; Z is C₁₋₄alkylene optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8substituents selected independently from the group consisting of C₁₋₃alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl, halogen and oxo; orZ is absent; R¹ is selected from the group consisting of H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl and C₃₋₇ cycloalkyl; R² is selected from thegroup consisting of H, C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆alkoxy, C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆alkylsulfonamide, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆alkylthio, C₁₋₆ alkylureyl, amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylcarboxamide, C₂₋₈ dialkylsulfonamide, halogen, C₁₋₆ haloalkoxy,C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆haloalkylthio, hydroxyl, thiol, nitro and sulfonamide; R³ is selectedfrom the group consisting of H, C₂₋₆ alkenyl, C₁₋₆ alkyl, C₁₋₆alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylcarboxamide, halogen, heteroaryl and phenyl; and wherein each ofsaid C₂₋₆ alkenyl, C₁₋₆ alkyl, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₃₋₇cycloalkyl, heteroaryl and phenyl groups are optionally substituted with1, 2, 3, 4, or 5 substituents selected independently from the groupconsisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₅alkyl, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl,C₁₋₄ alkylthio, C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₆ cycloalkyl, C₂₋₆ dialkylcarboxamide, halogen, C₁₋₄haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl, nitro and sulfonamide;R⁵, R⁶ and R⁷ are each selected independently from the group consistingof H, C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl,C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋₆ alkylamino, C₂₋₅ dialkylamino, C₁₋₆ alkylimino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈dialkylcarboxamide, C₂₋₅ dialkylsulfonamide, halogen, C₁₋₆ haloalkoxy,C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆ haloalkylsulfonyl, C₁₋₆haloalkylthio, heterocyclyl, hydroxyl, thiol, and nitro; and R⁸ isC₁₋₈-alkyl, aryl, C₃₋₁₀ cycloalkyl, heteroaryl, or heterocyclyl eachoptionally substituted with substituents selected independently from thegroup consisting of C₁₋₆ acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy,C₁₋₆ alkyl, C₁₋₆ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide,C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋₆ alkylamino, C₂₋₈ dialkylamino, C₁₋₆ alkylimino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₃₋₇cycloalkyloxy, C₂₋₈ dialkylcarboxamide, C₂₋₈ dialkylsulfonamide,halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, heteroaryl, heterocyclyl,hydroxyl, thiol, nitro, phenoxy and phenyl, wherein said C₂₋₆ alkenyl,C₁₋₆ alkyl, C₂₋₆ alkynyl, C₁₋₆ alkylamino, C₁₋₆ alkylimino, C₂₋₈dialkylamino, heteroaryl, heterocyclyl, phenyl, and phenoxy, and eachsaid substituent is optionally substituted with 1, 2, 3, 4, or 5substituents selected independently from the group consisting of C₁₋₆acyl, C₁₋₆ acyloxy, C₂₋₆ alkenyl, C₁₋₆ alkoxy, C₁₋₆ alkyl, C₁₋₆alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₆ alkylsulfonamide, C₁₋₆alkylsulfinyl, C₁₋₆ alkylsulfonyl, C₁₋₆ alkylthio, C₁₋₆ alkylureyl,amino, C₁₋₆ alkylamino, C₂₋₅ dialkylamino, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₈ dialkylcarboxamide,halogen, C₁₋₆ haloalkoxy, C₁₋₆ haloalkyl, C₁₋₆ haloalkylsulfinyl, C₁₋₆haloalkylsulfonyl, C₁₋₆ haloalkylthio, heterocyclyl, hydroxyl, thiol andnitro; and wherein the 5-HT_(2A) associated disorder is selected fromthe group consisting of: a sleep disorder, progressive multifocalleukoencephalopathy, hypertension, pain, claudication, peripheral arterydisease, vasoconstriction, vasospasm, thrombosis, and stroke.
 2. Themethod according to claim 1, wherein the compound has Formula (Ic):

wherein: R⁵, R⁶, and R⁷ are each H; V is O; and W is —CH₂CH₂— optionallysubstituted with 1 to 2 substituents selected independently from thegroup consisting of C₁₋₃ alkyl and oxo.
 3. The method according to claim2, wherein Q is —NR^(4a)R^(4b).
 4. The method according to claim 3,wherein R^(4a) is H; and R^(4b) is C₁₋₆ alkyl, C₃₋₇ cycloalkyl, C₁₋₆haloalkyl, heterocyclyl, or heteroaryl, wherein each is optionallysubstituted with 1, 2, 3, 4, or 5 substituents selected independentlyfrom the group consisting of C₁₋₄ alkoxy, C₁₋₅ alkyl, C₁₋₄alkylsulfonyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, cyano, hydroxyl,imino, and phenyl.
 5. The method according to claim 4, wherein R¹ isC₁₋₆ alkyl, R² is H, and R³ is H, Cl, or Br.
 6. The method according toclaim 5, wherein Z is absent and R⁸ is aryl, C₃₋₁₀ cycloalkyl, orheteroaryl each optionally substituted with substituents selectedindependently from the group consisting of C₁₋₆ alkoxy, C₁₋₆ alkyl,cyano, halogen, C₁₋₆ haloalkoxy, and C₁₋₆ haloalkyl.
 7. The methodaccording to claim 1, wherein the 5-HT2A associated disorder is a sleepdisorder.
 8. The method according to claim 1, wherein the 5-HT2Aassociated disorder is progressive multifocal leukoencephalopathy. 9.The method according to claim 1, wherein the 5-HT2A associated disorderis hypertension.
 10. The method according to claim 1, wherein the 5-HT2Aassociated disorder is pain.
 11. The method according to claim 1,wherein the 5-HT2A associated disorder is claudication.
 12. The methodaccording to claim 1, wherein the 5-HT2A associated disorder isperipheral artery disease.
 13. The method according to claim 1, whereinthe 5-HT2A associated disorder is vasoconstriction.
 14. The methodaccording to claim 1, wherein the 5-HT2A associated disorder isvasospasm.
 15. The method according to claim 1, wherein the 5-HT2Aassociated disorder is thrombosis.
 16. The method according to claim 1,wherein the 5-HT2A associated disorder is stroke.